Implantable therapeutic device

ABSTRACT

A therapeutic device to release a therapeutic agent comprises a porous structure coupled to a container comprising a reservoir. The reservoir comprises a volume sized to release therapeutic amounts of the therapeutic agent for an extended time when coupled to the porous structure and implanted in the patient. The porous structure may comprise a first side coupled to the reservoir and a second side to couple to the patient to release the therapeutic agent. The length of the channels extending from the first side to the second side may comprise an effective length greater than a distance across the porous structure from the first side to the second side. The therapeutic device may comprise a penetrable barrier to inject therapeutic agent into the device when implanted in the patient.

CROSS-REFERENCES TO RELATED APPLICATIONS

This patent application claims priority to U.S. Pat. App. Ser. Nos.61/371,169, filed 5 Aug. 2010, entitled “Implantable TherapeuticDevice”; 61/406,934, filed on 26 Oct. 2010, entitled “ImplantableTherapeutic Device”; 61/407,361, filed on 27 Oct. 2010, entitled“Implantable Therapeutic Device”; 61/371,136, filed 5 Aug. 2010,entitled “Expandable and Collapsible Therapeutic Delivery Apparatus andMethods”; and 61/371,154, entitled “Injector Apparatus and Method forDrug Delivery”, filed Aug. 5, 2010, the full disclosures of which areincorporated herein by reference.

This Continuation in Part patent application claims priority to U.S.patent application Ser. Nos.: 12/696,678 filed 29 Jan. 2010, entitled“Posterior Segment Drug Delivery”; 61/371,169, filed 5 Aug. 2010,entitled “Implantable Therapeutic Device”; 61/406,934, filed on 26 Oct.2010, entitled “Implantable Therapeutic Device”; and 61/407,361, filedon 27 Oct. 2010, entitled “Implantable Therapeutic Device”; 61/371,136,filed 5 Aug. 2010, entitled “Expandable and Collapsible TherapeuticDelivery Apparatus and Methods”; the full disclosures of which areincorporated herein by reference.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

NOT APPLICABLE

BACKGROUND OF THE INVENTION

The present invention relates to delivery of therapeutic agents to theposterior segment of the eye. Although specific reference is made to thedelivery of macromolecules comprising antibodies or antibody fragmentsto the posterior segment of the eye, embodiments of the presentinvention can be used to deliver many therapeutic agents to many tissuesof the body. For example, embodiments of the present invention can beused to deliver therapeutic agent to one or more of the followingtissues: intravascular, intra-articular, intrathecal, pericardial,intraluminal and gut.

The eye is critical for vision. The eye has a cornea and a lens thatform an image on the retina. The image formed on the retina is detectedby rods and cones on the retina. The light detected by the rods andcones of the retina is transmitted to the occipital cortex brain via theoptic nerve, such that the individual can see the image formed on theretina. Visual acuity is related to the density of rods and cones on theretina. The retina comprises a macula that has a high density of cones,such that the user can perceive color images with high visual acuity.

Unfortunately, diseases can affect vision. In some instances the diseaseaffecting vision can cause damage to the retina, even blindness in atleast some instances. One example of a disease that can affect vision isage-related macular degeneration (hereinafter AMD). Although therapeuticdrugs are known that can be provided to minimize degradation of theretina, in at least some instances the delivery of these drugs can beless than ideal.

In some instances a drug is injected into the eye through the sclera.One promising class of drugs for the treatment of AMD is known asvascular endothelial growth factor VEGF inhibitors. Unfortunately, in atleast some instances injection of drugs can be painful for the patient,involve at least some risk of infection and hemorrhage and retinaldetachment, and can be time consuming for the physician and patient.Consequently, in at least some instances the drug may be delivered lessoften than would be ideal, such that at least some patients may receiveless drug than would be ideal in at least some instances.

Work in relation to embodiments of the present invention also suggeststhat an injection of the drug with a needle results in a bolus deliveryof the drug, which may be less than ideal in at least some instances.For example, with a bolus injection of drug, the concentration of drugin the vitreous humor of the patient may peak at several times therequired therapeutic amount, and then decrease to below the therapeuticamount before the next injection.

Although some implant devices have been proposed, many of the knowndevices are deficient in at least some respects in at least someinstances. At least some of the known implanted devices do not providesustained release of a therapeutic drug for an extended period. Forexample, at least some of the known implanted devices may rely onpolymer membranes or polymer matrices to control the rate of drugrelease, and many of the known membranes and matrices may beincompatible with at least some therapeutic agents such as ionic drugsand large molecular weight protein drugs in at least some instances. Atleast some of the known semi-permeable polymer membranes may havepermeability that is less than ideal for the extended release of largemolecular weight proteins such as antibodies or antibody fragments.Also, work in relation to embodiments of the present invention alsosuggests that at least some of the known semi-permeable membranes canhave a permeability of large molecules that may vary over time and atleast some of the known semi-permeable membranes can be somewhatfragile, such that drug release for extended periods can be less thanideal in at least some instances. Although capillary tubes have beensuggested for drug release, work in relation to embodiments of thepresent invention suggests that flow through capillary tubes can be lessthan ideal in at least some instances, for example possibly due tobubble formation and partial clogging.

At least some of the known implantable devices can result in patientside effects in at least some instances when a sufficient amount of drugis delivered to treat a condition of the eye. For example, at least someof the commercially available small molecule drug delivery devices mayresult in patient side effects such as cataracts, elevated intraocularpressure, dizziness or blurred vision in at least some instances.Although corticosteroids and analogues thereof may be delivered with animplanted device to treat inflammation, the drug delivery profile can beless than ideal such that the patient may develop a cataract in at leastsome instances.

Although at least some of the proposed implanted devices may permit aninjection into the device, one potential problem is that an injectioninto an implanted device can cause at least some risk of infection forthe patient in at least some instances. Also, in at least some instancesthe drug release rate of an implanted device can change over time, suchthat the release rate of the drug can be less than ideal after injectionin at least some instance. At least some of the proposed implanteddevices may not be implanted so as to minimize the risk of infection tothe patient. For example, at least some of the proposed devices thatrely on pores and capillaries may allow microbes such as bacteria topass through the capillary and/or pore, such that infection may bespread in at least some instances. Also, work in relation to embodimentsof the present invention suggests that at least some of the proposedimplanted devices do not provide adequate protection from the patient'simmune system, such as from macrophages and antibodies, thereby limitingthe therapeutic effect in at least some instances.

At least some of the prior injection devices may not be well suited toinject an intended amount of a therapeutic agent into a therapeuticdevice implanted in the eye in at least some instances. For example, inat least some instances, coupling of the injector to the therapeuticdevice implanted in the eye may be less than ideal. Also, thetherapeutic device may provide resistance to flow such that injectioncan be difficult and may take more time than would be ideal or the flowinto the therapeutic device can be somewhat irregular in at least someinstances. The injector may decouple from the therapeutic device suchthat the amount of therapeutic agent delivered can be less than ideal inat least some instances. In at least some instances, the injectedtherapeutic agent may mix with a solution previously inside thetherapeutic device such that the amount of therapeutic agent thatremains in the device when the injection is complete can be more lessthan ideal in at least some instances.

In light of the above, it would be desirable to provide improvedtherapeutic devices and methods that overcome at least some of the abovedeficiencies of the known therapies, for example with improved drugrelease that can be maintained when implanted over an extended time.

SUMMARY OF THE INVENTION

Embodiments of the present invention provide methods and apparatus ofinjecting a formulation therapeutic agent into the body, for exampleinjection of the therapeutic agent into an implanted therapeutic devicesuch that the therapeutic agent is delivered from the therapeutic devicein therapeutic amounts for an extended time that can be at least about 1month. The injector apparatus can accurately inject intended amounts ofthe therapeutic agent into the therapeutic device, such that the amountof therapeutic agent inside the chamber reservoir of the device and theamount released into the eye correspond to substantially targetedamounts. The injector apparatus may comprise a coupling indicator toindicate when the injector apparatus is coupled to the therapeuticdevice and an injector apparatus extends a sufficient depth into thedevice for one or more of injection of the therapeutic agent or exchangeof the therapeutic agent with material within the therapeutic device.The reservoir chamber of the therapeutic device can be implanted in theeye such that the reservoir chamber is located under the sclera, betweenthe conjunctiva and the sclera, or under the sclera in the vitreoushumor, or combinations thereof.

In many embodiments, the therapeutic device is configured to providecontinuous release of therapeutic quantities of at least one therapeuticagent for an extended time of at least 3 months, for example 6 months,such that the frequency of injections into the therapeutic device andrisk of infection can be substantially decreased. In additionalembodiments, the therapeutic device is configured to provide continuousrelease of therapeutic quantities of at least one therapeutic agent foran extended time of at least 12 months, or at least 2 years or at least3 years.

The therapeutic device can be configured in many ways to release thetherapeutic agent for the extended time and may comprise at least one ofan opening, an elongate structure, a porous structure, or a poroussurface sized to release the therapeutic agent for the extended time.For example, the therapeutic device may comprise the porous structure torelease the therapeutic agent through the porous structure for theextended period. The porous structure may comprise a sintered materialhaving many channels, for example interconnecting channels, extendingaround many particles adhered to each other. The porous structure maycomprise a first side comprising a first plurality of openings coupledto the reservoir and a second side comprising a second plurality ofopenings to couple to the vitreous humor. The interconnecting channelsmay extend between each of the first plurality of openings of the firstside and each of the second plurality of openings of the second side soas to maintain release of the therapeutic agent through the porousstructure, for example when at least some the openings are blocked. Theporous structure can be rigid and maintain release of the therapeuticagent through the interconnecting channels when tissue or cells cover atleast a portion of the openings, for example when the porous structureis implanted for an extended time and the drug reservoir refilled.

The therapeutic device may comprise a retention structure configured tocouple to the sclera to position the container for delivery of thetherapeutic agent into the vitreous humor of the eye, such that theconjunctiva may extend over the retention structure when the device isimplanted so as to inhibit the risk of infection to the patient andallow access to the device with decreased risk of infection. Forexample, the retention structure may comprise a flange extending outwardfor placement between the conjunctiva and sclera and a narrow portion tofit within the incision through the sclera. The narrow portion to fitthe incision may comprise an elongate cross sectional profile sized tofit the incision. The elongate cross-sectional profile sized to fit theincision can improve the fit of the implanted device to the scleralincision, and may seal the implant against the sclera along theincision. The elongate cross sectional profile of the narrow portion canbe sized in many ways to fit the incision. For example, the elongatecross section may comprises a first dimension longer than a seconddimension and may comprise one or more of many shapes such as dilatedslit, dilated slot, lentoid, oval, ovoid, or elliptical. The dilatedslit shape and dilated slot shape may correspond to the shape scleratissue assumes when cut and dilated. The lentoid shape may correspond toa biconvex lens shape. The elongate cross-section of the narrow portionmay comprise a first curve along an first axis and a second curve alonga second axis different than the first curve.

In many embodiments, the reservoir of the therapeutic device isflushable and/or refillable. This provides the added benefit that thephysician may remove the therapeutic agent from the patient by flushingthe agent from the reservoir of the therapeutic device rather thanwaiting for the therapeutic agent to be eliminated from the patient.This removal can be advantageous in cases where the patient has anadverse drug reaction or benefit from a pause in therapy sometimesreferred to as a drug holiday. The volume of the reservoir and releaserate of the porous structure can be tuned to receive a volume of acommercially available formulation, such that the therapeutic agent canbe released for an extended time. For example, the volume ofcommercially available therapeutic agent may correspond to a bolusinjection having a treatment duration, for example one month, and thereservoir volume and release rate tuned to receive the formulationvolume can extend the treatment duration of the injected volume by afactor of at least about two, for example from one month to two or moremonths.

In a first aspect, embodiments provide a method of treating an eyehaving a vitreous humor. At least about 3.5 mg of ranibizumab isinjected into a therapeutic device implanted in the eye, and the amountcan be within a range from about 3.5 to about 5.5 mg, for example about4.5 mg. The therapeutic device has a chamber volume sized to store nomore than about 1.5 mg of ranibizumab, for example no more than about2.5 mg, such that at least about 2 mg of ranibizumab is released fromthe therapeutic device to the vitreous humor of the eye as a bolusinjection.

In many embodiments, at least about 4 mg of ranibizumab is injected intothe therapeutic device implanted in the eye, such that at least about 2mg of ranibizumab is released from the therapeutic device to thevitreous humor of the eye as a second bolus injection.

In another aspect, embodiments provide a method of treating an eyehaving a vitreous humor. A first amount of a therapeutic agent isinjected into a therapeutic device implanted in the eye. A second amountof the therapeutic agent is injected into the therapeutic deviceimplanted in the eye. The second amount can be less than the firstamount based on a portion of the amount of therapeutic agent containedin the therapeutic device when the second amount is injected.

In many embodiments, the second amount is less than the first amountbased on a mixing ratio of the second amount with the portion.

In many embodiments, the second amount is injected at least about onemonth after the first amount is injected.

In another aspect, embodiments provide method of treating an eye havinga vitreous humor. A first amount of a therapeutic agent is injected intoa therapeutic device implanted in the eye. The first amount correspondsto a first injection volume greater than a chamber volume of thetherapeutic device, such that a first portion of the first amount ispassed through the chamber into the vitreous humor as a first bolusinjection and a second contained portion is contained in the chamber andreleased for an extended time. A second amount of the therapeutic agentis injected into the therapeutic device implanted in the eye, and thesecond amount corresponds to a second injection volume greater than thechamber volume of the therapeutic device, such that a first portion ofthe second amount is passed through the chamber into the vitreous humoras a second bolus injection and a second contained portion is containedin the chamber and released for an extended time. The second amount canbe less than the first amount such that the second bolus injection hasno more therapeutic agent than the first bolus injection.

In another aspect, embodiments provide a method of treating an eyehaving a vitreous humor. An amount of therapeutic agent is injected intoa reservoir of a therapeutic device. The reservoir has a substantiallyfixed volume coupled to a porous structure. The amount may be greaterthan the substantially fixed volume, such that a first portion of theamount is released into the vitreous humor of the eye as a bolusinjection and a second portion of the amount is retained in thereservoir. The second portion may be released from the porous structureat amounts lower than amounts of the first portion, such that the bolusinjection corresponds to a maximum concentration of the therapeuticagent in the eye.

In many embodiments, the maximum concentration comprises no more than apeak concentration of corresponding to an amount of the bolus injection.

In another aspect, embodiments provide a method of treating an eyehaving a vitreous humor and an established safe bolus amount of atherapeutic agent. A first amount of a therapeutic agent is injectedinto a therapeutic device implanted in the eye. A second amount of thetherapeutic agent is injected into the therapeutic device implanted inthe eye. A portion of the first amount of therapeutic agent is containedin the therapeutic device when the second amount is injected such that asecond bolus is released from the therapeutic device to the vitreoushumor, the second bolus comprising a second amount of the therapeuticagent greater than the established safe bolus amount.

In many embodiments, the second amount comprises an incremental increasein exposure to the therapeutic agent.

In many embodiments, further comprising injecting additional bolusamounts above the second amount to establish a second safe bolus amount.

In many embodiments, further comprising removing the therapeutic agentfrom the therapeutic device based on a negative response to the secondamount of the therapeutic agent, wherein the therapeutic agent isexchanged with a solution substantially lacking the therapeutic agent.

In another aspect, embodiments provide an apparatus to treat an eye aneye with a therapeutic agent having an established safe amount. Aninjector has a volume of liquid comprising an amount of therapeuticagent. A therapeutic device has a chamber volume sized smaller than theinjector volume to release a bolus of the therapeutic agent.

In another aspect, embodiments provide a sustained drug deliveryformulation comprising a therapeutic agent wherein the therapeutic agentis contained in a reservoir of the device as described above, and thetherapeutic agent has a half-life within the reservoir when implanted.The half life within the reservoir is substantially greater than acorresponding half-life of the at least one of the therapeutic agentwhen injected directly into the vitreous of an eye.

In many embodiments, the device can be configured by selection of thereservoir volume and a porous structure with an appropriate rate releaseindex to achieve the desired effective half-life.

In many embodiments, the rate release index of the porous structure isfrom about 0.001 to about 5, for example from about 0.002 to about 5,and can be from about 0.01 to about 5.

In many embodiments, the first therapeutic agent is a VEGF-inhibitor andthe second therapeutic agent is an inflammatory response inhibitor.

In another aspect, embodiments provide sustained drug deliveryformulation to treat a patient of a population. The formulationcomprises a therapeutic agent, and the therapeutic agent has a half-lifewithin the eye corresponding to a half life the therapeutic agentinjected into a device implanted in the eye.

In another aspect, embodiments provide a method of treating an eye. Anamount therapeutic agent is injected into a therapeutic device, and theamount within a range from about 0.01 mg to about 50 mg, and the rangecan be from about 0.1 mg to about 30 mg.

In another aspect, embodiments provide an apparatus to treat an eye. Theapparatus comprises an amount of formulation corresponding to an amountof therapeutic agent, in which the amount within a range from about 0.01mg to about 50 mg, and the range can be from about 0.1 to about 30 mg. Atherapeutic device has a reservoir chamber and porous structure tuned toreceive the amount of formulation corresponding to the amount oftherapeutic agent.

In many embodiments, the amount is within a range is from about 0.1 mgto about 30 mg.

In another aspect, embodiments provide an apparatus to treat an eye witha therapeutic agent. The apparatus comprises an injector having a volumeof fluid comprising an amount of therapeutic agent. A therapeutic devicecomprises a reservoir chamber, and the reservoir chamber has a volumesized to receive the amount of therapeutic agent. The amount oftherapeutic agent is placed in the reservoir chamber.

In many embodiments, the fluid comprises a concentration of ranibizumabwithin a range from about 40 mg/mL to about 200 mg/mL, for examplewithin a range from about 40 mg/ml to about 100 mg/mL.

In many embodiments, the injector is configured to place the amount withno substantial bolus.

In many embodiments, the injector is configured to place the amount withan exchange efficiency of at least about 80%.

In many embodiments, the injector comprises an injection lumen to injectthe therapeutic and a vent to receive fluid of the chamber, thetherapeutic device comprises a reservoir chamber to release thetherapeutic agent. The vent may comprise a resistance to flowsubstantially lower than a resistance to flow of the porous structure ofthe therapeutic device so as to inhibit a bolus of the therapeutic agentthrough the porous structure.

In another aspect, embodiments provide an apparatus to treat an eye aneye with a therapeutic agent. A volume of a fluid comprising an amountof therapeutic agent is injected into a therapeutic device comprising areservoir chamber. The reservoir chamber has a volume sized to receivethe amount of therapeutic agent, and the amount of therapeutic agent isplaced in the reservoir chamber.

In many embodiments, the injector is configured to place the amount withan exchange efficiency of at least about 80%.

In many embodiments, the amount is placed in the reservoir chamber withno substantial bolus of the fluid comprising the therapeutic agentthrough the porous structure.

In another aspect, embodiments provide an expandable and collapsibletherapeutic device having a substantially fixed volume. The therapeuticdevice may comprise a first narrow profile configuration for placement,and a second expanded wide profile configuration to deliver the drugwith the reservoir when positioned in the eye. The expanded devicehaving one or more support structures can be collapsed, for examplecompressed or extended to decrease cross sectional size, such that thedevice can fit through the incision. For example, the therapeutic devicemay comprise a flexible barrier material coupled to a support, such thatthe barrier material and support can be expanded from a first narrowprofile configuration to the second expanded profile configuration, andsubsequently collapsed to the first narrow profile configuration forremoval. The support can provide a substantially constant reservoirvolume in the expanded configuration, such that the device can be tunedwith the porous structure and expandable reservoir to receive the volumeof therapeutic agent formulation and so as to release therapeuticamounts for the extended time. The therapeutic device may comprise aporous barrier extending around the container with channels sized topass the therapeutic agent from the container therethrough and toinhibit migration of at least one of a bacterial cell out of thecontainer or a macrophage or other immune cell into the container. Toremove the therapeutic device having the flexible barrier coupled to thesupport, the support can be collapsed at least partially for removal,for example with elongation along an axis of the therapeutic device suchthat the cross sectional size of the support is decreased for removalthrough the incision. In many embodiments, a proximal end of thetherapeutic device is coupled to a removal apparatus, and an elongatestructure couples to a distal portion of the therapeutic device and isextended along such that the distal portion is urged distally and thecross sectional size of the support decreased for removal through theincision. The elongate structure may comprise one or more of a needle, ashaft, a mandrel or a wire, and the distal portion may comprise a stopcoupled to the support such as the porous structure or a portion of thesupport, such that the support is extended along the axis for removalwhen the elongate structure is advanced distally.

In many embodiments, a removal apparatus comprises the elongatestructure and jaws to couple to the retention structure and wherein theelongate structure comprises one or more of a needle, a shaft, a mandrelor a wire.

In many embodiments, the porous structure comprises a rigid porousstructure affixed to a distal end of the support to release thetherapeutic agent into a vitreous humor of the eye for an extended time.The flexible support and flexible barrier may comprise flexibilitysufficient to increase the length increases from the second length tothe first length when the elongate structure contacts the rigid porousstructure.

In many embodiments, the support comprises a plurality of flexiblestruts that extend axially from the retention structure to an annularflange sized to support the porous structure on the distal end ofdevice, and wherein the flexible struts comprise are space apart whenthe device comprises the second expanded profile configuration to definethe chamber having the substantially constant volume.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an eye suitable for incorporation of the therapeuticdevice, in accordance with embodiments of the present invention;

FIG. 1A-1 shows a therapeutic device implanted at least partially withinthe sclera of the eye as in FIG. 1;

FIG. 1A-1-1 and 1A-1-2 show a therapeutic device implanted under theconjunctiva and extending through the sclera to release a therapeuticagent into vitreous humor of the eye so as to treat the retina of the,in accordance with embodiments of the present invention;

FIG. 1A-2 shows structures of a therapeutic device configured forplacement in an eye as in FIGS. 1A-1 and 1A-1-1, according toembodiments of the present invention;

FIG. 1A-2-1 shows a therapeutic device loaded into an insertion cannula,in which the device comprises an elongate narrow shape for insertioninto the sclera, and in which the device is configured to expand to asecond elongate wide shape for retention at least partially in thesclera;

FIG. 1A-2-2 shows a therapeutic device comprising a reservoir suitablefor loading in a cannula;

FIG. 1B shows a therapeutic device configured for placement in an eye asin FIGS. 1A-1 and 1A-1-1, in accordance with embodiments of the presentinvention;

FIG. 1C shows a therapeutic device configured for placement in an eye asin FIGS. 1A-1 and 1A-1-1, in accordance with embodiments of the presentinvention;

FIG. 1C-A shows at least one exit port, according to embodiments of thepresent invention;

FIG. 1C-1 shows a method of removing a binding material, according toembodiments of the present invention;

FIG. 1C-2 and inserting the therapeutic agent with a second inserthaving the TA bound thereon;

FIG. 1C-3 shows syringe being filled with a commercially availableformulation of therapeutic agent for injection into the therapeuticdevice, in accordance with embodiments;

FIG. 1D shows a therapeutic device configured for placement in an eye asin FIG. 1A-1 and 1A-1-1, in which the device comprises a plurality ofchambers and channels connecting the chambers so as to linearize therelease of the therapeutic agent;

FIG. 1E shows a therapeutic device configured for placement in an eye asin FIGS. 1A-1 and 1A-1-1, in which the device comprises a needle stoplocated at the bottom of the therapeutic device;

FIG. 1E-1 shows a therapeutic device configured for placement in an eyeas in FIGS. 1A-1 and 1A-1-1, in which the device comprises a needle stoplocated at the bottom of the therapeutic device and the shape of thedevice encourages the movement of the therapeutic agent within thechamber of the therapeutic device;

FIG. 1E-2 shows a therapeutic device configured for placement in an eyeas in FIGS. 1A-1 and 1A-1-1, in which the device comprises a needle stoplocated in the middle of the therapeutic device;

FIG. 1E-3 shows a therapeutic device configured for placement in an eyeas in FIGS. 1A-1 and 1A-1-1, in which the device comprises a needle stoplocated in the middle of the therapeutic device and the shape of thedevice encourages the movement of the therapeutic agent within thechamber of the therapeutic device;

FIG. 1E-3-1 shows a top view of the therapeutic device configured forplacement in an eye as in FIGS. 1E-3;

FIG. 2 shows an access port suitable for incorporation with thetherapeutic device, in accordance with embodiments of the presentinvention;

FIG. 3A shows a collar suitable for incorporation with the therapeuticdevice, in accordance with embodiments of the present invention;

FIG. 3B shows biocompatible material impregnated with an anti-bacterialagent on the therapeutic device to inhibit bacterial growth along thedevice from the sclera to the vitreous humor;

FIG. 4A shows released fragments of antibodies, and FIG. 4B showsantibody fragments reversibly bound to a substrate, in accordance withembodiments of the present invention;

FIG. 5A shows a therapeutic device coupled to an injector to inserttherapeutic agent into the device;

FIG. 5A-1 shows a therapeutic device coupled to an injector tosimultaneously inject and remove material from the device;

FIG. 5B shows a therapeutic device comprising a micro loop channel;

FIG. 5C-1 shows a therapeutic device comprising a tortuous channel;

FIG. 5C-2 shows a therapeutic device comprising a coiled channel;

FIG. 5D shows an expandable and contractible structure to retain thetherapeutic agent and an outer rigid casing to couple to the sclera;

FIG. 5E shows a membrane disposed over an exit port of a therapeuticdevice;

FIG. 5F shows a therapeutic device comprising a tubular membrane clampedonto the therapeutic device;

FIG. 6A-1 shows a therapeutic device comprising a container having apenetrable barrier disposed on a first end, a porous structure disposedon a second end to release therapeutic agent for an extended period, anda retention structure comprising an extension protruding outward fromthe container to couple to the sclera and the conjunctiva;

FIG. 6A-2 shows a therapeutic device as in FIG. 6A comprising a roundeddistal end;

FIG. 6B shows a rigid porous structure configured for sustained releasewith a device as in FIG. 6A;

FIG. 6B-1 shows interconnecting channels extending from a first side toa second side of the porous structure as in FIG. 6B;

FIG. 6B-2 shows a plurality of paths of the therapeutic agent along theinterconnecting channels extending from a first side to a second side ofthe porous structure as in FIGS. 6B and 6B1;

FIG. 6B-3 shows blockage of the openings with a covering and theplurality of paths of the therapeutic agent along the interconnectingchannels extending from a first side to a second side of the porousstructure as in FIGS. 6B and 6B-1;

FIG. 6B-4 shows blockage of the openings with particles and theplurality of paths of the therapeutic agent along the interconnectingchannels extending from a first side to a second side of the porousstructure as in FIGS. 6B and 6B-1;

FIG. 6B-5 shows an effective cross-sectional size and area correspondingto the plurality of paths of the therapeutic agent along theinterconnecting channels extending from a first side to a second side ofthe porous structure as in FIGS. 6B and 6B-1;

FIG. 6C shows a rigid porous structure as in FIG. 6B incorporated into ascleral tack;

FIG. 6D, shows a rigid porous structure as in FIG. 6B coupled with areservoir for sustained release;

FIG. 6E shows a rigid porous structure as in FIG. 6B comprising a hollowbody or tube for sustained release;

FIG. 6F shows a rigid porous structure as in FIG. 6B comprising anon-linear helical structure for sustained release;

FIG. 6G shows porous nanostructures, in accordance with embodiments;

FIG. 7 shows a therapeutic device coupled to an injector that removesmaterial from the device and injects therapeutic agent into the device,according to embodiments;

FIG. 7A shows a therapeutic device comprising a porous structure and apenetrable barrier as in FIG. 6E, with the penetrable barrier coupled toan injector to inject and remove material from the device, in accordancewith embodiments;

FIG. 7A-1 shows a therapeutic device coupled to an injector needlecomprising a stop that positions the distal end of the needle near theproximal end of the device to flush the reservoir with ejection ofliquid formulation through the porous frit structure, in accordance withembodiments;

FIG. 7A-2 shows a therapeutic device comprising a penetrable barriercoupled to an injector to inject and remove material from the devicesuch that the liquid in the reservoir is exchanged with the injectedformulation, in accordance with embodiments;

FIG. 7A-3 shows a deformable visual indicator;

FIG. 7A-4 shows the visual indicator coupled to soft tissue, such astissue of an eye, for example the conjunctiva positioned over thepenetrable barrier of the therapeutic device;

FIG. 7A-5 shows a therapeutic device 100 coupled to injector 701 withone or more of potentially insufficient force prior to injection orpotentially insufficient depth;

FIG. 7A-6 shows a therapeutic device 100 coupled to injector 701 withone or more of potentially insufficient force prior to injection orpotentially insufficient depth;

FIG. 7A-7A to FIG. 7A-9B show sliding coupling of a valve to a plungercoupled to a piston to exchange a first intended volume of liquid withinthe reservoir with a volume of formulation of therapeutic agent andclose the valve so as to inject a second volume of liquid through theporous frit structure;

FIG. 7A-10A and FIG. 7A-10B show a first configuration of an injector tomaintain the rate of flow into device to within about +/−50%, forexample to within about +/−25%, such that the time to inject thetherapeutic agent into device 100 remains substantially constant amongdevices and injections;

FIG. 7B-1 shows a side cross-sectional view of a therapeutic devicecomprising a retention structure having a cross-section sized to fit inan elongate incision, in accordance with embodiments;

FIG. 7B-2 shows an isometric view of the therapeutic device as in FIG.7B-1;

FIG. 7B-3 shows a top view of the therapeutic device as in FIG. 7B-1;

FIG. 7B-4 shows a side cross sectional view along the short side of theretention structure of the therapeutic device as in FIG. 7B-1;

FIG. 7B-5 shows a bottom view of the therapeutic device as in FIG. 7B-1implanted in the sclera;

FIG. 7B-5A shows a cutting tool comprising a blade having a widthcorresponding to the perimeter of the barrier and the perimeter of thenarrow retention structure portion;

FIGS. 7B-6A and 7B-6B show distal cross-sectional view and a proximalcross-sectional view, respectively, of a therapeutic device comprisingan elongate and non-circular cross-sectional size, in accordance withembodiments;

FIG. 7B-6C shows an isometric view of the therapeutic device having aretention structure with an elongate cross-sectional size, in accordancewith embodiments;

FIG. 7B-6D shows a distal end view of the therapeutic device as in FIG.7B-6C;

FIG. 7B-6E1 shows a side view of the short axis of the narrow neckportion of the therapeutic device as in FIG. 7B-6C;

FIG. 7B-6E2 shows a side view of the long axis of the narrow neckportion of the therapeutic device as in FIG. 7B-6C;

FIG. 7B-6F shows a proximal view of the therapeutic device as in FIGS.7B-6C;

FIG. 7B-6G to FIG. 7B-6I show exploded assembly drawings for thetherapeutic device as in FIGS. 7B-6C to 7B-6F;

FIG. 7C-1 shows an expandable therapeutic device comprising anexpandable barrier material and support in an expanded configuration forextended release of the therapeutic agent, in accordance withembodiments;

FIG. 7C-1A shows the distal end portion of the support 160S as in FIG.7C-1;

FIG. 7C-1B shows the support 160S disposed inside the barrier 160, inaccordance with embodiments;

FIG. 7C-1C shows the support 160S disposed along the inner surface ofthe barrier 160, in accordance with embodiments;

FIG. 7C-1D shows an elongate structure of a removal apparatus insertedinto the expandable and collapsible cross-section device to decrease thecross-sectional width of the device;

FIG. 7C-1E shows the first elongate profile configuration of support160S comprising first length L1 and first width W1; and

FIG. 7C-1F shows the second wide profile configuration of support 160Scomprising second length L2 and second width W2;

FIG. 7C-2 shows the expandable therapeutic device as in FIG. 7C1 in anarrow profile configuration;

FIG. 7C-3 shows the expandable therapeutic device as in FIG. 7C1 in anexpanded profile configuration;

FIGS. 7C-4A and 7C-4B show an expandable retention structure, inaccordance with embodiments;

FIG. 7D shows a therapeutic device comprising a porous structurepositioned in an eye to deliver a therapeutic agent to a target locationon the retina, in accordance with embodiments

FIG. 7E shows a therapeutic device comprising a porous structure locatedon the device to deliver a therapeutic agent to one or more of theciliary body or the trabecular meshwork when positioned in the eye, inaccordance with embodiments;

FIG. 7F shows therapeutic device 100 comprising porous structure 150oriented to release the therapeutic agent away from the lens and towardthe retina, in accordance with embodiments;

FIG. 7G shows a kit comprising a placement instrument, a container, anda therapeutic device within the container, in accordance withembodiments;

FIG. 8 show reservoirs with exit ports of defined diameters fabricatedfrom 1 mL syringes with Luer-Lok™ tips and needles of varying diameter,in accordance with embodiments;

FIG. 8-1 shows the needles attached to syringes as in FIG. 8;

FIG. 8-2 shows the reservoirs placed into vials;

FIG. 9 shows cumulative release through the needles of varying diameter;

FIG. 10 shows release rate as a function of area;

FIG. 11 shows a reservoir with a porous membrane fabricated by cuttingoff the Luer-Lok tip on a 1 mL syringe;

FIG. 11-1 shows the delivery rates from two replicates of a reservoir asin FIG. 11;

FIG. 12 shows the cumulative release of fluorescein through cut-offneedles;

FIG. 13 shows the cumulative release of BSA protein through a sinteredporous titanium cylinder;

FIG. 13-1 shows the measured cumulative release of BSA of FIG. 13measured to 180 days;

FIG. 14 shows the cumulative release of BSA protein through a maskedsintered porous titanium cylinder at Condition 1, in accordance withexperimental embodiments;

FIG. 15 shows cumulative release of BSA protein through a maskedsintered porous titanium cylinder at Condition 2, in accordance withexperimental embodiments;

FIG. 16 shows cumulative release of BSA protein through a maskedsintered porous titanium cylinder at Condition 3, in accordance withexperimental embodiments;

FIG. 17 shows cumulative release of BSA through 0.1 media grade sinteredporous stainless steel cylinder;

FIG. 18A shows cumulative release of BSA through 0.2 media gradesintered porous stainless steel cylinder;

FIG. 18B shows cumulative release of BSA through 0.2 media gradesintered porous stainless steel cylinder for 180 days;

FIG. 19A compares calculated Lucentis™ pharmacokinetics profiles to thepharmacokinetics profiles predicted for the device in Example 8;

FIG. 19B shows determined concentrations of ranibizumab in the vitreoushumor for a first 50 uL Lucentis™ injection into a 25 uL reservoir ofthe device and a second 50 uL injection at 90 days, in accordance withembodiments;

FIG. 19C shows determined concentrations of ranibizumab in the vitreoushumor for a first 50 uL Lucentis™ injection into a 32 uL reservoir ofthe device and a second 50 uL injection at 90 days, in accordance withembodiments;

FIG. 19D shows determined concentrations of ranibizumab in the vitreoushumor for a first 50 uL Lucentis™ injection into a 50 uL reservoir ofthe device and a second 50 uL injection at 90 days, in accordance withembodiments;

FIG. 19E shows determined concentrations of ranibizumab in the vitreoushumor for a first 50 uL Lucentis™ injection into a 50 uL reservoir ofthe device and a second 50 uL injection at 130 days, in accordance withembodiments;

FIG. 19F shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 50 uL device having arelease rate index of 0.05, in accordance with embodiments;

FIG. 19G shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 75 uL device having arelease rate index of 0.05, in accordance with embodiments;

FIG. 19H shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 100 uL device having arelease rate index of 0.05, in accordance with embodiments;

FIG. 19I shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 125 uL device having arelease rate index of 0.05, in accordance with embodiments;

FIG. 19J shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 150 uL device having arelease rate index of 0.05, in accordance with embodiments;

FIG. 19K shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 100 uL device having arelease rate index of 0.1, in accordance with embodiments;

FIG. 19L shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.105, in accordance withembodiments;

FIG. 19M shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.095, in accordance withembodiments;

FIG. 19N shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.085, in accordance withembodiments;

FIG. 19O shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.075, in accordance withembodiments;

FIG. 19P shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.065, in accordance withembodiments;

FIG. 19Q shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL concentrated Lucentis™ (40 mg/mL) injection into a 10uL device having a release rate index of 0.01 and in which theranibizumab has a half life in the vitreous humor of about nine days, inaccordance with embodiments;

FIG. 19R shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL concentrated Lucentis™ (40 mg/mL) injection into a 10uL device having a release rate index of 0.01 and in which theranibizumab has a half life in the vitreous humor of about five days, inaccordance with embodiments;

FIG. 19S shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL standard Lucentis™ (10 mg/mL) injection into a 10 uLdevice having a release rate index of 0.01 and in which the ranibizumabhas a half life in the vitreous humor of about nine days, in accordancewith embodiments;

FIG. 19T shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL standard Lucentis™ (10 mg/mL) injection into a 10 uLdevice having a release rate index of 0.01 and in which the ranibizumabhas a half life in the vitreous humor of about five days, in accordancewith embodiments;

FIG. 20 shows a calculated time release profile of a therapeutic agentsuspension in a reservoir, in accordance with embodiments.

FIG. 21 shows cumulative release for Avastin™ with therapeutic devicescomprising substantially similar porous frit structures and a 16 uLreservoir and a 33 uL reservoir;

FIG. 22A shows cumulative release for Avastin™ with porous fritstructures having a thickness of 0.049″;

FIG. 22B-1 shows cumulative release for Avastin™ with porous fitstructures having a thickness of 0.029″;

FIG. 22B-2 shows rate of release for Avastin™ with porous fit structureshaving a thickness of 0.029″ as in FIG. 22B-1;

FIG. 23A shows cumulative release for Avastin™ with a reservoir volumeof 20 uL;

FIG. 23A-1 shows cumulative release to about 90 days for Avastin™ with areservoir volume of 20 uL as in FIG. 23A;

FIG. 23B shows rate of release as in FIG. 23A;

FIG. 23B-1 shows rate of release as in FIG. 23A-1;

FIG. 24A shows cumulative release for Avastin™ with a 0.1 media gradeporous fit structure;

FIG. 24A-1 shows cumulative release to about 90 days release forAvastin™ with a 0.1 media grade porous frit structure as in FIG. 24A;

FIG. 24B shows rates of release of the devices as in FIG. 24A;

FIG. 24B-1 shows rates of release of the devices as in FIG. 24A-1;

FIG. 25A shows cumulative release for fluorescein through a 0.2 mediagrade porous frit structure;

FIG. 25A-1 shows cumulative release to about 90 days for fluoresceinthrough a 0.2 media grade porous fit structure as in FIG. 25A;

FIG. 25B shows rates of release of the devices as in FIG. 25A;

FIG. 25B-1 shows rates of release of the devices as in FIG. 25A-1;

FIG. 25C shows cumulative release to about thirty days for Lucentis™through a 0.2 media grade porous frit structure having a diameter of0.038 in and a length (thickness) of 0.029 in.;

FIG. 25D shows rates of release of the devices as in FIG. 25C;

FIG. 25E shows cumulative release to about thirty days for Lucentis™ for30 uL devices having a RRI's from about 0.015 to about 0.090;

FIG. 25F shows rates of release of the devices as in FIG. 25E;

FIGS. 25E1 and 25F1 shows an update of Lucentis drug release studies inFIGS. 25E and 25F, respectively, measured up to 6 months;

FIGS. 26A and 26B show scanning electron microscope images fromfractured edges of porous frit structures so as to show the structure ofthe porous structure to release the therapeutic agent, in accordancewith embodiments;

FIGS. 27A and 27B show scanning electron microscope images from surfacesof porous frit structures, in accordance with embodiments;

FIG. 28 shows a pressure decay test and test apparatus for use with aporous structure so as to identify porous frit structures suitable foruse with therapeutic devices in accordance with embodiments describedherein;

FIG. 29 shows a pressure flow test and test apparatus suitable for usewith a porous structure so as to identify porous frit structuressuitable for use with therapeutic devices in accordance with embodimentsdescribed herein;

FIG. 30A-1 shows an example of an OCT macular cube OCT image used toidentify a region of interest (black arrow) and determine the responseto treatment;

FIGS. 30B-1, 30B-2 and 30B-3 show an example of a series of OCT scanimages at pre-injection, one day post-injection and one weekpost-injection, respectively, of sections of the region of interest;

FIGS. 31A and 31B shows experimental implantation of therapeutic deviceinto the pars plana region 25 of a rabbit eye with visualization of thedevice sealing the elongate incision under the flange and dark fieldvisualization of the implanted therapeutic device;

FIG. 32A shows the concentration profile of monthly bolus injections of2 mg of ranibizumab directly into the vitreous humor as compared with aninjection into the device 100 comprising 4.5 mg ranibizumab such that2.5 mg of ranibizumab are stored in the device and 2 mg of ranibizumabare injected into the eye through the porous structure 150;

FIG. 32B shows the concentration profile of monthly bolus injections of2 mg of ranibizumab directly into the vitreous humor as compared with aplurality of injections into the device 100 comprising 4.5 mgranibizumab such that 2.5 mg of ranibizumab are stored in the device and2 mg of ranibizumab are injected into the eye through the porousstructure 150;

FIG. 32C shows the plurality of ranibizumab injections of 4.5 mg and themonthly bolus injections of 2 mg as in FIG. 32B as compared with monthlybolus injections of 0.5 mg of commercially available and approvedLucentis™;

FIGS. 32D and 32E show injections with amounts into the device 100 andbolus injections similar to FIGS. 32A to 32C, in which the injectionsare performed at 6 months;

FIGS. 33A and 33A1 show a side cross sectional view and a top view,respectively, of therapeutic device 100 for placement substantiallybetween the conjunctiva and the sclera;

FIG. 33A2 shows the therapeutic device 100 implanted with the reservoirbetween the conjunctiva and the sclera, such that elongate structure 172extends through the sclera to couple the reservoir chamber to thevitreous humor;

FIG. 33B shows the porous structure 150 of therapeutic device 100located in channel 174 near the opening to the chamber of the container130;

FIG. 33C shows the porous structure 150 located within the chamber ofcontainer 150 and coupled to the first opening of the elongate structure172 so as to provide the release rate profile;

FIG. 33D shows a plurality of injection ports spaced apart so as toinject and exchange the liquid of chamber of the container 130 andinject the therapeutic agent into the reservoir chamber of the container130;

FIG. 34 shows the elongate structure 172 coupled to the container 130away from the center of container 130 and near and located near an endof the container;

FIG. 35 shows stability data for a formulation of Lucentis that can beused to identify materials for porous frit structures, in accordancewith embodiments

FIG. 36A shows amounts of ranibizumab released at about 90 days for a100 mg/mL formulation of Ranibizumab and the corresponding reservoirchamber volume from about 10 uL to about 50 uL and the corresponding RRIfrom about 0.01 to about 0.08;

FIG. 36B shows amounts of ranibizumab released at about 180 days for a100 mg/mL formulation of Ranibizumab and the corresponding reservoirchamber volume from about 10 uL to about 50 uL and the corresponding RRIfrom about 0.01 to about 0.08;

FIG. 36C shows amounts of ranibizumab released at about 90 days for a 10mg/mL formulation of Ranibizumab and the corresponding reservoir chambervolume from about 10 uL to about 50 uL and the corresponding RRI fromabout 0.01 to about 0.08;

FIG. 36D shows amounts of ranibizumab released at about 180 days for a10 mg/mL formulation of Ranibizumab and the corresponding reservoirchamber volume from about 10 uL to about 50 uL and the corresponding RRIfrom about 0.01 to about 0.08;

FIG. 37 shows vitreous humor concentration profiles corresponding toranibizumab formulations of 40 mg/mL and 100 mg/mL injected into thetherapeutic device, in accordance with embodiments;

FIG. 37A shows release of Ranibizumab formulations to 180 days from atherapeutic device comprising an RRI of 0.02 and a volume of 25 uLcorresponding to an effective half life of the therapeutic agent in thedevice of 100 days;

FIG. 37B shows release of Ranibizumab to 180 days from a therapeuticdevice comprising an RRI of 0.008 and a volume of 25 uL corresponding toan effective half life of the therapeutic agent in the device of 250days, in accordance with embodiments; and

FIG. 37C shows release of ranibizumab from a population of devicesreceiving injections of 40 mg/mL formulation and 100 mg/mL formulation,in accordance with embodiments.

DETAILED DESCRIPTION OF THE INVENTION

Although specific reference is made to the delivery of macromoleculescomprising antibodies or antibody fragments to the posterior segment ofthe eye, embodiments of the present invention can be used to delivermany therapeutic agents to many tissues of the body. For example,embodiments of the present invention can be used to deliver therapeuticagent for an extended period to one or more of the following tissues:intravascular, intra articular, intrathecal, pericardial, intraluminaland gut.

Embodiments of the present invention provide sustained release of atherapeutic agent to the posterior segment of the eye or the anteriorsegment of the eye, or combinations thereof. Therapeutic amounts of atherapeutic agent can be released into the vitreous humor of the eye,such that the therapeutic agent can be transported by at least one ofdiffusion or convection to the retina or other ocular tissue, such asthe choroid or ciliary body, for therapeutic effect.

As used herein the release rate index encompasses (PA/FL) where Pcomprises the porosity, A comprises an effective area, F comprises acurve fit parameter corresponding to an effective length and L comprisesa length or thickness of the porous structure. The units of the releaserate index (RRI) comprise units of mm unless indicated otherwise and canbe determine by a person of ordinary skill in the art in accordance withthe teachings described hereon.

As used herein, sustained release encompasses release of therapeuticamounts of an active ingredient of a therapeutic agent for an extendedperiod of time. The sustained release may encompass first order releaseof the active ingredient, zero order release of the active ingredient,or other kinetics of release such as intermediate to zero order andfirst order, or combinations thereof.

As used herein a therapeutic agent referred to with a trade nameencompasses one or more of the formulation of the therapeutic agentcommercially available under the tradename, the active ingredient of thecommercially available formulation, the generic name of the activeingredient, or the molecule comprising the active ingredient.

As used herein, similar numerals indicate similar structures and/orsimilar steps.

The therapeutic agent may be contained within a chamber of a container,for example within a reservoir comprising the container and chamber. Thetherapeutic agent may comprise a formulation such as solution oftherapeutic agent, a suspension of a therapeutic agent or a dispersionof a therapeutic agent, for example. Examples of therapeutic agentssuitable for use in accordance with embodiments of the therapeuticdevice are described herein, for example with reference to Table 1Abelow and elsewhere.

The therapeutic agent may comprise a macromolecule, for example anantibody or antibody fragment. The therapeutic macromolecule maycomprise a VEGF inhibitor, for example commercially available Lucentis™.The VEGF (Vascular Endothelial Growth Factor) inhibitor can causeregression of the abnormal blood vessels and improvement of vision whenreleased into the vitreous humor of the eye. Examples of VEGF inhibitorsinclude Lucentis™, Avastin™, Macugen™, and VEGF Trap.

The therapeutic agent may comprise small molecules such as of acorticosteroid and analogues thereof. For example, the therapeuticcorticosteroid may comprise one or more of trimacinalone, trimacinaloneacetonide, dexamethasone, dexamethasone acetate, fluocinolone,fluocinolone acetate, or analogues thereof. Alternatively or incombination, the small molecules of therapeutic agent may comprise atyrosine kinase inhibitor comprising one or more of axitinib, bosutinib,cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib,lestaurtinib, nilotinib, semaxanib, sunitinib, toceranib, vandetanib, orvatalanib, for example.

The therapeutic agent may comprise an anti-VEGF therapeutic agent.Anti-VEGF therapies and agents can be used in the treatment of certaincancers and in age-related macular degeneration. Examples of anti-VEGFtherapeutic agents suitable for use in accordance with the embodimentsdescribed herein include one or more of monoclonal antibodies such asbevacizumab (Avastin™) or antibody derivatives such as ranibizumab(Lucentis™), or small molecules that inhibit the tyrosine kinasesstimulated by VEGF such as lapatinib (Tykerb™), sunitinib (Sutent™),sorafenib (Nexavar™), axitinib, or pazopanib.

The therapeutic agent may comprise a therapeutic agent suitable fortreatment of dry AMD such as one or more of Sirolimus™ (Rapamycin),Copaxone™ (Glatiramer Acetate), Othera™, Complement C5aR blocker,Ciliary Neurotrophic Factor, Fenretinide or Rheopheresis.

The therapeutic agent may comprise a therapeutic agent suitable fortreatment of wet AMD such as one or more of REDD14NP (Quark), Sirolimus™(Rapamycin), ATG003; Regeneron™ (VEGF Trap) or complement inhibitor(POT-4).

The therapeutic agent may comprise a kinase inhibitor such as one ormore of bevacizumab (monoclonal antibody), BIBW 2992 (small moleculetargeting EGFR/Erb2), cetuximab (monoclonal antibody), imatinib (smallmolecule), trastuzumab (monoclonal antibody), gefitinib (smallmolecule), ranibizumab (monoclonal antibody), pegaptanib (smallmolecule), sorafenib (small molecule), dasatinib (small molecule),sunitinib (small molecule), erlotinib (small molecule), nilotinib (smallmolecule), lapatinib (small molecule), panitumumab (monoclonalantibody), vandetanib (small molecule) or E7080 (targetingVEGFR2/VEGFR2, small molecule commercially available from Esai, Co.)

The amount of therapeutic agent within the therapeutic device maycomprise from about 0.01 mg to about 50 mg, for example Lucentis™, so asto provide therapeutic amounts of the therapeutic agent for the extendedtime, for example at least 30 days. The extended time may comprise atleast 90 days or more, for example at least 180 days or for example atleast 1 year, at least 2 years or at least 3 years or more. The targetthreshold therapeutic concentration of a therapeutic agent such asLucentis™ in the vitreous may comprise at least a therapeuticconcentration of 0.1 ug/mL. For example the target thresholdconcentration may comprise from about 0.1 ug/mL to about 5 ug/mL for theextended time, where the upper value is based upon calculations shown inExample 9 using published data. The target threshold concentration isdrug dependent and thus may vary for other therapeutic agents.

The delivery profile may be configured in many ways to obtain atherapeutic benefit from the sustained release device. For example, anamount of the therapeutic agent may be inserted into the container atmonthly intervals so as to ensure that the concentration of therapeuticdevice is above a safety protocol or an efficacy protocol for thetherapeutic agent, for example with monthly or less frequent injectionsinto the container. The sustained release can result in an improveddelivery profile and may result in improved results. For example, theconcentration of therapeutic agent may remain consistently above athreshold amount, for example 0.1 ug/mL, for the extended time.

The insertion method may comprise inserting a dose into the container ofthe therapeutic device. For example, a single injection of Lucentis™ maybe injected into the therapeutic device.

The duration of sustained delivery of the therapeutic agent may extendfor twelve weeks or more, for example four to six months from a singleinsertion of therapeutic agent into the device when the device isinserted into the eye of the patient.

The therapeutic agent may be delivered in many ways so as to provide asustained release for the extended time. For example, the therapeuticdevice may comprise a therapeutic agent and a binding agent. The bindingagent may comprise small particles configured to couple releasably orreversibly to the therapeutic agent, such that the therapeutic agent isreleased for the extended time after injection into the vitreous humor.The particles can be sized such that the particles remain in thevitreous humor of the eye for the extended time.

The therapeutic agent may be delivered with a device implanted in theeye. For example, the drug delivery device can be implanted at leastpartially within the sclera of the eye, so as to couple the drugdelivery device to the sclera of the eye for the extended period oftime. The therapeutic device may comprise a drug and a binding agent.The drug and binding agent can be configured to provide the sustainedrelease for the extended time. A membrane or other diffusion barrier ormechanism may be a component of the therapeutic device to release thedrug for the extended time.

The lifetime of the therapeutic device and number of injections can beoptimized for patient treatment. For example, the device may remain inplace for a lifetime of 30 years, for example with AMD patients fromabout 10 to 15 years. For example, the device may be configured for animplantation duration of at least two years, with 8 injections (onceevery three months) for sustained release of the therapeutic agent overthe two year duration. The device may be configured for implantation ofat least 10 years with 40 injections (once every three months) forsustained release of the therapeutic agent.

The therapeutic device can be refilled in many ways. For example, thetherapeutic agent can be refilled into the device in the physician'soffice.

The therapeutic device may comprise many configurations and physicalattributes, for example the physical characteristics of the therapeuticdevice may comprise at least one of a drug delivery device with asuture, positioning and sizing such that vision is not impaired, andbiocompatible material. The device may comprise a reservoir capacityfrom about 0.005 cc to about 0.2 cc, for example from about 0.01 cc toabout 0.1 cc, and a device volume of no more than about 2 cc. Avitrectomy may be performed for device volumes larger than 0.1 cc. Thelength of the device may not interfere with the patient's vision and canbe dependent on the shape of the device, as well as the location of theimplanted device with respect to the eye. The length of the device mayalso depend on the angle in which the device is inserted. For example, alength of the device may comprise from about 4 to 6 mm. Since thediameter of the eye is about 24 mm, a device extending no more thanabout 6 mm from the sclera into the vitreous may have a minimal effecton patient vision.

Embodiments may comprise many combinations of implanted drug deliverydevices. The therapeutic device may comprise a drug and binding agent.The device may also comprise at least one of a membrane, an opening, adiffusion barrier, a diffusion mechanism so as to release therapeuticamounts of therapeutic agent for the extended time.

FIG. 1 shows an eye 10 suitable for incorporation of the therapeuticdevice. The eye has a cornea 12 and a lens 22 configured to form animage on the retina 26. The cornea can extend to a limbus 14 of the eye,and the limbus can connect to a sclera 24 of the eye. A conjunctiva 16of the eye can be disposed over the sclera. The lens can accommodate tofocus on an object seen by the patient. The eye has an iris 18 that mayexpand and contract in response to light. The eye also comprises achoroid 28 disposed the between the sclera 24 and the retina 26. Theretina comprises the macula 32. The eye comprises a pars plana 25, whichcomprises an example of a region of the eye suitable for placement andretention, for example anchoring, of the therapeutic device 100 asdescribed herein. The pars plana region may comprise sclera andconjunctiva disposed between the retina and cornea. The therapeuticdevice can be positioned so as to extend from the pars plana region intothe vitreous humor 30 to release the therapeutic agent. The therapeuticagent can be released into the vitreous humor 30, such that thetherapeutic agent arrives at the retina and choroids for therapeuticeffect on the macula. The vitreous humor of the eye comprises a liquiddisposed between the lens and the retina. The vitreous humor maycomprise convection currents to deliver the therapeutic agent to themacula.

FIG. 1A-1 shows a therapeutic device 100 implanted at least partiallywithin the sclera 24 of the eye 10 as in FIG. 1. The therapeutic devicemay comprise a retention structure, for example a protrusion, to couplethe device to the sclera. The therapeutic device may extend through thesclera into vitreous humor 30, such that the therapeutic device canrelease the therapeutic agent into the vitreous humor.

FIGS. 1A-1-1 and 1A-1-2 shows a therapeutic device 100 implanted underthe conjunctiva 16 and extending through the sclera 24 to release atherapeutic agent 110 into vitreous humor 30 of the eye 10 so as totreat the retina of the eye. The therapeutic device 100 may comprise aretention structure 120 such as a smooth protrusion configured forplacement along the sclera and under the conjunctiva, such that theconjunctiva can cover the therapeutic device and protect the therapeuticdevice 100. When the therapeutic agent 110 is inserted into the device100, the conjunctiva may be lifted away, incised, or punctured with aneedle to access the therapeutic device. The eye may comprise aninsertion of the tendon 27 of the superior rectus muscle to couple thesclera of the eye to the superior rectus muscle. The device 100 may bepositioned in many locations of the pars plana region, for example awayfrom tendon 27 and one or more of posterior to the tendon, posterior tothe tendon, under the tendon, or with nasal or temporal placement of thetherapeutic device.

While the implant can be positioned in the eye in many ways, work inrelation to embodiments suggests that placement in the pars plana regioncan release therapeutic agent into the vitreous to treat the retina, forexample therapeutic agent comprising an active ingredient composed oflarge molecules.

Therapeutic agents 110 suitable for use with device 100 includes manytherapeutic agents, for example as listed in Table 1A, herein below. Thetherapeutic agent 110 of device 100 may comprise one or more of anactive ingredient of the therapeutic agent, a formulation of thetherapeutic agent, a commercially available formulation of thetherapeutic agent, a physician prepared formulation of therapeuticagent, a pharmacist prepared formulation of the therapeutic agent, or acommercially available formulation of therapeutic agent having anexcipient. The therapeutic agent may be referred to with generic name ora trade name, for example as shown in Table 1A.

The therapeutic device 100 can be implanted in the eye to treat the eyefor as long as is helpful and beneficial to the patient. For example thedevice can be implanted for at least about 5 years, such as permanentlyfor the life of the patient. Alternatively or in combination, the devicecan be removed when no longer helpful or beneficial for treatment of thepatient.

FIG. 1A-2 shows structures of therapeutic device 100 configured forplacement in an eye as in FIGS. 1A-1, 1A-1-1 and 1A-1-2. The device maycomprise retention structure 120 to couple the device 100 to the sclera,for example a protrusion disposed on a proximal end of the device. Thedevice 100 may comprise a container 130 affixed to the retentionstructure 120. An active ingredient, for example therapeutic agent 110,can be contained within a reservoir 140, for example a chamber 132defined by a container 130 of the device. The container 130 may comprisea porous structure 150 comprising a porous material 152, for example aporous glass frit 154, and a barrier 160 to inhibit release of thetherapeutic agent, for example non-permeable membrane 162. Thenon-permeable membrane 162 may comprise a substantially non-permeablematerial 164. The non-permeable membrane 162 may comprise an opening 166sized to release therapeutic amounts of the therapeutic agent 110 forthe extended time. The porous structure 150 may comprise a thickness150T and pore sizes configured in conjunction with the opening 166 so asto release therapeutic amounts of the therapeutic agent for the extendedtime. The container 130 may comprise reservoir 140 having a chamber witha volume 142 sized to contain a therapeutic quantity of the therapeuticagent 110 for release over the extended time. The device may comprise aneedle stop 170. Proteins in the vitreous humor may enter the device andcompete for adsorption sites on the porous structure and thereby maycontribute to the release of therapeutic agent. The therapeutic agent110 contained in the reservoir 140 can equilibrate with proteins in thevitreous humor, such that the system is driven towards equilibrium andthe therapeutic agent 110 is released in therapeutic amounts.

The non-permeable membrane 162, the porous material 152, the reservoir140, and the retention structure 120, may comprise many configurationsto deliver the therapeutic agent 110. The non-permeable membrane 162 maycomprise an annular tube joined by a disc having at least one openingformed thereon to release the therapeutic agent. The porous material 152may comprise an annular porous glass fit 154 and a circular end disposedthereon. The reservoir 140 may be shape-changing for ease of insertion,i.e. it may assume a thin elongated shape during insertion through thesclera and then assume an extended, ballooned shape, once it is filledwith therapeutic agent.

The porous structure 150 can be configured in many ways to release thetherapeutic agent in accordance with an intended release profile. Forexample, the porous structure may comprise a porous structure having aplurality of openings on a first side facing the reservoir and aplurality of openings on a second side facing the vitreous humor, with aplurality of interconnecting channels disposed therebetween so as tocouple the openings of the first side with the openings of the secondside, for example a sintered rigid material. The porous structure 150may comprise one or more of a permeable membrane, a semi-permeablemembrane, a material having at least one hole disposed therein,nano-channels, nano-channels etched in a rigid material, laser etchednano-channels, a capillary channel, a plurality of capillary channels,one or more tortuous channels, tortuous microchannels, sinterednano-particles, an open cell foam or a hydrogel such as an open cellhydrogel.

FIG. 1A-2-1 shows therapeutic device 100 loaded into an insertioncannula 210 of an insertion apparatus 200, in which the device 100comprises an elongate narrow shape for insertion into the sclera, and inwhich the device is configured to expand to a second elongate wide shapefor retention at least partially in the sclera;

FIG. 1A-2-2 shows a therapeutic device 100 comprising reservoir 140suitable for loading in a cannula, in which the reservoir 140 comprisesan expanded configuration.

FIG. 1B shows therapeutic device 100 configured for placement in an eyeas in FIG. 1A-1 and 1A-1-1. The device comprises retention structure 120to couple to the sclera, for example flush with the sclera, and thebarrier 160 comprises a tube 168. An active ingredient 112 comprisingthe therapeutic agent 110 is contained within tube 168 comprisingnon-permeable material 164. A porous material 152 is disposed at thedistal end of the tube 168 to provide a sustained release of thetherapeutic agent at therapeutic concentrations for the extended period.The non-permeable material 164 may extend distally around the porousmaterial 152 so as to define an opening to couple the porous material152 to the vitreous humor when the device is inserted into the eye.

The tube 168 and retention structure 120 may be configured to receive aglass rod, which is surface treated, and the glass rod can be injectedwith therapeutic agent. When the therapeutic agent has finished elutionfor the extended time, the rod can be replaced with a new rod.

The device 100 may comprise therapeutic agent and a carrier, for examplea binding medium comprising a binding agent to deliver the therapeuticagent. The therapeutic agent can be surrounded with a column comprisinga solid support that is eroded away.

FIG. 1C shows a therapeutic device configured for placement in an eye asin FIG. 1A-1 and 1A-1-1. A binding medium 192 comprising a binding agent190 such as glass wool may be loaded with therapeutic agent 110 prior toinjection into the device through an access port 180. The device 100 maycomprise binding, leak, and barrier functions to deliver the therapeuticagent for the extended time. The binding medium 192 and therapeuticagent 110 can be aspirated to replace the binding medium and therapeuticagent. The binding medium can be at least one of flushed or replacedwhen at least majority of the therapeutic agent has been released, suchthat additional therapeutic agent can be delivered from a second,injected binding medium comprising therapeutic agent. A membrane 195 canbe disposed over the periphery of the therapeutic device 100. Themembrane 195 may comprise methylcellulose, regenerated cellulose,cellulose acetate, nylon, polycarbonate, poly(tetrafluoroethylene)(PTFE), polyethersulfone, and polyvinylidene difluoride (PVDF). Thetherapeutic device may comprise barrier 160 shaped such that opening 166comprises an exit port. The therapeutic agent may be released through atleast one of a diffusion mechanism or convection mechanism. The number,size, and configuration of exit ports may determine the release rate ofthe therapeutic agent. The exit port may comprise a convection port, forexample at least one of an osmotically driven convection port or aspring driven convection port. The exit port may also comprise a tubularpath to which the therapeutic agent may temporarily attach, and then bereleased under certain physical or chemical conditions.

FIG. 1C-A shows at least one exit port 167, the exit port can bedisposed on the device 100 to allow liquid to flow from inside thedevice outward, for example when fluid is injected into an injectionport 182 of the device or when an insert such as a glass frit isinserted into the device. The therapeutic device may comprise an accessport 180 for injection and/or removal, for example a septum.Additionally or in the alternative, when the therapeutic device isrefilled, the contents of the device may be flushed into the vitreous ofthe eye.

FIG. 1C-1 shows a method of removing a binding agent 194. A needle 189coupled to a syringe 188 of an injector 187 can be inserted into anaccess port 180 of the therapeutic device 100. The binding agent 194 canbe aspirated with a needle.

FIG. 1C-2 shows a method of inserting the therapeutic agent 110 with asecond binding agent 190 having the therapeutic agent 110 bound thereon.The therapeutic agent can be injected into a container 130 of the devicefor sustained release over the extended time.

FIG. 1C-3 shows syringe being filled with a formulation of therapeuticagent for injection into the therapeutic device. The needle 189 coupledto syringe 188 of injector 187 can be used to draw therapeutic agent 110from a container 110C. The container 110C may comprise a commerciallyavailable container, such as a bottle with a septum, a single dosecontainer, or a container suitable for mixing formulations. A quantity110V of therapeutic agent 110 can be drawn into injector 187 forinjection into the therapeutic device 100 positioned within the eye. Thequantity 110V may comprise a predetermined quantity, for example basedon the volume of the container of the therapeutic device 110 and anintended injection into the vitreous humor. The example the quantity110V may exceed the volume of the container so as to inject a firstportion of quantity 110V into the vitreous humor through the therapeuticdevice and to contain a second portion of quantity 110V within thecontainer of the therapeutic device 110. Container 110C may comprise aformulation 110F of the therapeutic agent 110. The formulation 110F maycomprise a commercially available formulations of therapeutic agent, forexample therapeutic agents as described herein and with reference toTable 1A. Non-limiting examples of commercially available formulationsthat may be suitable for use in accordance with the embodimentsdescribed herein include Lucentis™ and Triamcinolone, for example. Theformulation 110F may be a concentrated or diluted formulation of acommercially available therapeutic agent, for example Avastin™. Theosmolarity and tonicity of the vitreous humor can be within a range fromabout 290 to about 320. For example, a commercially availableformulation of Avastin™ may be diluted so as to comprise a formulationhaving an osmolarity and tonicity substantially similar to theosmolarity and tonicity of the vitreous humor, for example within arange from about 280 to about 340, for example about 300 mOsm. While thetherapeutic agent 110 may comprise an osmolarity and tonicitysubstantially similar to the vitreous humor, the therapeutic agent 110may comprise a hyper osmotic solution relative to the vitreous humor ora hypo osmotic solution relative to the vitreous humor. A person orordinary skill in the art can conduct experiments based on the teachingsdescribed herein so as to determine empirically the formulation andosmolarity of the therapeutic agent to provide release of therapeuticagent for an extended time.

For example, in the United States of America, Lucentis™ (activeingredient ranibizumab) is supplied as a preservative-free, sterilesolution in a single-use glass vial designed to deliver 0.05 mL of 10mg/mL Lucentis™ aqueous solution with 10 mM histidine HCl, 10%α,α-trehalose dihydrate, 0.01% polysorbate 20, at pH 5.5. In Europe, theLucentis™ formulation can be substantially similar to the formulation ofthe United States.

For example, the sustained release formulation of Lucentis™ indevelopment by Genentech and/or Novartis, may comprise the therapeuticagent injected in to the device 100. The sustained release formulationmay comprise particles comprising active ingredient.

For example, in the United States, Avastin™ (bevacizumab) is approved asan anticancer drug and in clinical trials are ongoing for AMD. Forcancer, the commercial solution is a pH 6.2 solution for intravenousinfusion. Avastin™ is supplied in 100 mg and 400 mg preservative-free,single-use vials to deliver 4 mL or 16 mL of Avastin™ (25 mg/mL). The100 mg product is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mgsodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate(dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for Injection,USP. The 400 mg product is formulated in 960 mg α,α-trehalose dihydrate,92.8 mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodiumphosphate (dibasic, anhydrous), 6.4 mg polysorbate 20, and Water forInjection, USP. The commercial formulations are diluted in 100 mL of0.9% sodium chloride before administration and the amount of thecommercial formulation used varies by patient and indication. Based onthe teachings described herein, a person of ordinary skill in the artcan determine formulations of Avastin™ to inject into therapeutic device100. In Europe, the Avastin™ formulation can be substantially similar tothe formulation of the United States.

For example, in the United States, there are 2 forms of Triamcinoloneused in injectable solutions, the acetonide and the hexacetonide. Theacetamide is approved for intravitreal injections in the U.S. Theacetamide is the active ingredient in TRIVARIS (Allergan), 8 mgtriamcinolone acetonide in 0.1 mL (8% suspension) in a vehiclecontaining w/w percents of 2.3% sodium hyaluronate; 0.63% sodiumchloride; 0.3% sodium phosphate, dibasic; 0.04% sodium phosphate,monobasic; and water, pH 7.0 to 7.4 for injection. The acetamide is alsothe active ingredient in Triesence™ (Alcon), a 40 mg/ml suspension.

A person of ordinary skill in the art can determine the osmolarity forthese formulations. The degree of dissociation of the active ingredientin solution can be determined and used to determined differences ofosmolarity from the molarity in these formulations. For example,considering at least some of the formulations may be concentrated (orsuspensions), the molarity can differ from the osmolarity.

The formulation of therapeutic agent injected into therapeutic device100 may comprise many known formulations of therapeutic agents, and theformulation therapeutic agent comprises an osmolarity suitable forrelease for an extended time from device 100. Table 1B shows examples ofosmolarity (Osm) of saline and some of the commercially formulations ofTable 1A.

TABLE 1B Summary of Calculations Description Osm (M) Saline (0.9%) 0.308Phosphate Buffered Saline (PBS) 0.313 Lucentis ™ 0.289 Avastin ™ 0.182Triamcinolone Acetonide (Trivaris-Allergan) 0.342 TriamcinoloneAcetonide (Triessence - Alcon) Isotonic* Triamcinolone Acetonide(Kenalog - Apothecon) Isotonic* *As described in package insert

The vitreous humor of the eye comprises an osmolarity of about 290 mOsmto about 320 mOsm. Formulations of therapeutic agent having anosmolarity from about 280 mOsm to about 340 mOsm are substantiallyisotonic and substantially iso-osmotic with respect to the vitreoushumor of the eye. Although the formulations listed in Table 1B aresubstantially iso-osmotic and isotonic with respect to the vitreous ofthe eye and suitable for injection into the therapeutic device, theformulation of the therapeutic agent injected into the therapeuticdevice can be hypertonic (hyper-osmotic) or hypotonic (hypo-osmotic)with respect to the tonicity and osmolarity of the vitreous. Work inrelation to embodiments suggests that a hyper-osmotic formulation mayrelease the active ingredient of the therapeutic agent into the vitreoussomewhat faster initially when the solutes of the injected formulationequilibrate with the osmolarity of the vitreous, and that a hypo-osmoticformulation such as Avastin™ may release the active ingredient of thetherapeutic agent into the vitreous somewhat slower initially when thesolutes of the injected formulation equilibrate with the eye. A personof ordinary skill in the art can conduct experiments based on theteaching described herein to determine empirically the appropriatereservoir chamber volume and porous structure for a formulation oftherapeutic agent disposed in the reservoir chamber, so as to releasetherapeutic amounts of the therapeutic agent for an extended time and toprovide therapeutic concentrations of therapeutic agent in the vitreouswithin a range of therapeutic concentrations that is above the minimuminhibitory concentration for the extended time.

FIG. 1D shows a therapeutic device 100 configured for placement in aneye as in FIG. 1A-1 and 1A-1-1, in which the device comprises aplurality of chambers and channels connecting the chambers so as tolinearize the release of the therapeutic agent. A first chamber 132A maycomprise a reservoir having a first volume to contain the therapeuticquantity of the therapeutic agent. For example, the therapeutic agentcomprises the active ingredient contained within the reservoir. A secondchamber 132B can be disposed distally to the first chamber, with a firstopening connecting the first chamber and the second chamber. Thetherapeutic agent can diffuse through the first opening into the secondchamber. The second chamber comprises a second volume, such thattherapeutic agent is temporarily stored in the second chamber so as tolinearize, for example toward zero order, the delivery of thetherapeutic agent. A second opening can extend from the second chambertoward the vitreous humor. The first opening, the second opening and thesecond volume can be sized so as to linearize the delivery of thetherapeutic agent for the sustained release at therapeutic levels forthe extended time. More than one therapeutic agent can be inserted intothe therapeutic device. In such a case the two or more therapeuticagents may be mixed together or injected into separate chambers.

Additional chambers and openings can be disposed on the device tolinearize the delivery of the drug. For example, a third chamber can bedisposed distally to the second chamber. The second opening can couplethe second chamber to the third chamber. For example, a fourth chambercan be disposed distally to the third chamber, a third opening canconnect the third chamber and the fourth chamber.

Additionally or in the alternative, the therapeutic device may compriseat least one gate to provide for sustained drug delivery. The gate canbe moved from “closed” to “open” position using magnetism or by applyingelectrical current. For example the gates can slide or twist. The gatescan be spring-loaded, and may comprise a pump that can be re-loaded. Thegates may comprise an osmotic pump.

FIG. 1E shows a therapeutic device configured for placement in an eye asin FIGS. 1A-1 and 1A-1-1, in which the device comprises 100 needle stop170 located at the bottom of the therapeutic device. The needle stopthat may be included in the therapeutic device to keep the injectionneedle 189 from penetrating through and possibly damaging the exitport(s) 166 of the therapeutic device 100. The needle stop willdesirably be made of a material of sufficient rigidity to prevent theadvancement of the injection needle past a certain level in thetherapeutic device. Additionally or in the alternative, the length ofthe injector's needle may be designed so that it may not penetratethrough and possibly damage the exit port(s) of the therapeutic device.

As shown in FIGS. 1E and 1E-1, the needle stop 170 may be positioned atthe posterior end of the therapeutic device. FIGS. 1E-2, 1E-3 and 1E-3-1show other embodiments that may include needle stops placed in themiddle of the device. The needle stop may be designed in such a manneras to function as a flow diverter for the therapeutic agent. The shapeof the needle stop may encourage the mixing of the therapeutic agentwith the rest of the fluids present in the inner chamber(s) of thetherapeutic device.

FIG. 1E-1 shows a therapeutic device configured for placement in an eyeas in FIGS. 1A-1 and 1A-1-1, in which the device comprises needle stop170 located at the bottom of the therapeutic device and the shape of thedevice encourages the movement of the therapeutic agent within thechamber of the therapeutic device 100;

FIG. 1E-2 shows a therapeutic device configured for placement in an eyeas in FIGS. 1A-1 and 1A-1-1, in which the device comprises needle stop170 located in the middle of the therapeutic device;

FIG. 1E-3 shows a therapeutic device configured for placement in an eyeas in FIGS. 1A-1 and 1A-1-1, in which the device comprises needle stop170 located in the middle of the therapeutic device and the shape of thedevice encourages the movement of the therapeutic agent within thechamber of the therapeutic device;

FIG. 1E-3-1 shows a top view of the therapeutic device configured forplacement in an eye as in FIGS. 1E-3;

FIG. 2 shows an access port 180 suitable for incorporation with thetherapeutic device 100. The access port 180 may be combined with thetherapeutic devices described herein, for example with reference toFIGS. 1A-1 to 1D. The access port may be disposed on a proximal end ofthe device. The access port 180 may comprise an opening formed in theretention structure 120 with a penetrable barrier 184 comprising aseptum 186 disposed thereon. The access port may 180 be configured forplacement under the conjunctiva 16 of the patient and above the sclera24.

FIG. 3A shows a collar 128 suitable for incorporation with thetherapeutic device 100. The retention structure 120 configured to coupleto the sclera 24 may comprise the collar 128. The collar may comprise anexpandable collar.

FIG. 3B shows biocompatible material impregnated with an anti-bacterialagent 310 on the therapeutic device 100 to inhibit bacterial growthalong the device from the sclera to the vitreous humor. Thebiocompatible material may comprise collagen, for example a collagensponge 312, and the anti-bacterial agent may comprise silver impregnatedin the collagen. The biocompatible material impregnated with thebactericide agent may extend around at least a portion of the outersurface of the device. The anti-bacterial agent may comprise a portionof the retention structure 120, such that the anti-bacterial agent isdisposed at least partially within the sclera when the device isinserted into the eye.

FIG. 4A shows released antibodies comprising antibody fragments 410 anda substrate 420 comprising binding agent 190, and FIG. 4B shows anantibody fragments 410 reversibly bound to a substrate 420 with bindingagent 190, in accordance with embodiments of the present invention. Theanti-body fragments can be reversibly bound to the substrate comprisingthe binding agent, such that the bound antibody fragments are inequilibrium with the unbound antibody fragments. One of ordinary skillin the art will recognize many substrates comprising binding agent toreversibly bind at least a portion of an antibody based on the teachingsdescribed herein. Examples of binding media may include particulatesused in chromatography, such as: Macro-Prep t-Butyl HIC Support,Macro-Prep DEAE Support, CHT Ceramic, Hydroxyapatite Type I, Macro-PrepCM Support, Macro-Prep Methyl HIC Support, Macro-Prep CeramicHydroxapatite Type II, UNOsphere S Cation Exchange Support, UNOsphere QStrong Anion Exchange Support, Macro-Prep High-S Support, and Macro-PrepHigh-Q Support. Additional media to test for binding include ionexchange and bioaffinity chromatography media based on a hydrophilicpolymeric support (GE Healthcare) that bind proteins with high capacity,and a hydrophilic packing material from Harvard Apparatus made frompoly(vinyl alcohol) that binds more protein than silica. Othercandidates would be known to those knowledgeable in the art.

FIG. 5A shows therapeutic device 100 coupled to injector 187 to inserttherapeutic agent 110 into container 130 of the device. The injector 187may comprise needle 189 coupled to a syringe 188.

FIG. 5A-1 shows a therapeutic device 100 coupled to an injector 187 toinject and remove material from the device. The injector may compriseneedle 189 having a first lumen 189A and a second lumen 189B configuredto insert into a container of the device. The injector maysimultaneously inject 510 therapeutic agent into and withdraw 520 liquidfrom the device. The injector may comprise a first one way valve and asecond one way valve coupled to the first lumen and the second lumen,respectively.

FIG. 5B shows a therapeutic device comprising a microloop channel 530.The microloop channel may extend to a first port 530A and a second port530B, such the therapeutic agent can be injected into the first port,for example with a binding agent, and flowable material, for exampleliquid comprising binding agent, can be drawn from the microloop channel530.

FIG. 5C-1 shows therapeutic device 100 comprising a tortuous channel540. The tortuous channel may comprise extend from a first port 540A toa second port 540B, such that the therapeutic agent can be injected intothe first port and flowable material, for example liquid comprising thebinding agent, can be drawn from the second channel.

FIG. 5C-2 shows a therapeutic device comprising a tortuous coiledchannel 550. The coiled channel 550 can extend to an exit port 552. Aneedle 189 can be inserted into the port 180 to inject therapeutic agentinto device 100.

FIG. 5D shows an expandable and contactable structure 562 to retain thetherapeutic agent and an outer rigid casing 560 to couple to the sclera.The expandable structure 562 may comprise a membrane, such as at leastone of a bag, a balloon, a flexible reservoir, a diaphragm, or a bag.The outer rigid casing may extend substantially around the structure 562and may comprise an opening to release liquid into the vitreous humorwhen the structure is expanded and to draw vitreous humor inside achamber of the casing when material is drawn from the structure and thestructure contacts.

FIG. 5E shows a membrane 550 disposed over an exit port 552 oftherapeutic device 100.

FIG. 5F shows therapeutic device 100 comprising a tubular membrane 572clamped onto the therapeutic device over side ports 570 of device 100.

When the protective membranes have pores of 0.2 um diameter, they are 20or more times larger than the proteins of interest, which may comprise amodel for delivery of the therapeutic agent. For example, molecularweights and diameters of models of proteins of therapeutic interest are:

(a) IgG 150 kDa 10.5 nm (b) BSA  69 kDa  7.2 nm (c) Fab fragment of  49kDa hydrodynamic IgG diameter not reported

Therefore, solutions of therapeutic compounds in the size range of IgGand BSA should flow relatively easily through 0.2 um pore sizeprotective membranes used to stop passage of bacterial and other cells.

Binding Materials/Agents may comprise at least one of a chemical bindingagent/material, a structural binding agent or material, or anelectrostatic binding agent or material. The types of binding agent maycomprise a classification composed of non-biodegradable material, forexample at glass beads, glass wool or a glass rod. A surface can bederivatized with at least one functional group so as to impart thebinding agent or material with the potential for at least one of ionic,hydrophobic, or bioaffinity binding to at least one therapeuticcompound.

The binding agent may comprise a biodegradable material. For example,the biodegradation, binding, or a combination of the previous processesmay control the diffusion rate.

The binding agent may comprise ion exchange, and the ion exchange maycomprise at least one of a functional group, a pH sensitive binding or apositive or negative charge. For example, ion exchange with at least oneof diethylaminoethyl or carboxymethyl functional groups.

The binding agent may comprise a pH sensitive binding agent. For examplethe binding agent can be configured to elute therapeutic agent at a pHof 7, and to bind the therapeutic agent at a pH from about 4 to about6.5. A cation exchange binding agent can be configured, for example,such that at a pH of 7, the net negative charge of the binding agentdecreases causing a decrease in binding of the positively charged drugand release of the therapeutic agent. A target buffer can be providedwith the binding agent to reversibly couple the binding agent to thetherapeutic agent. The rate of release can be controlled, for exampleslowed down, by using insolubility of the buffer in the vitreous.Alternatively or in combination the elution can be limited by using aporous membrane or a physical property such as a size of an opening.

The ion exchange may comprise positive or negative ion exchange.

The binding agent may comprise hydrophobic interaction. For example, thebinding agent may comprise at least one binding to hydrophobic pockets,for example at least one of methyl, ethyl, propyl, butyl, t-butyl orphenyl functional groups.

The binding agent may comprise affinity, for example at least one of amacromolecular affinity or a metal chelation affinity. Examples caninclude a hydroxyapatite, or chelated metal, for example zinc.Iminodiacetic acid can be chelated with zinc.

The binding agent may comprise at least one of the following functions:charging, recharging or elution. The charging may comprise a porousmaterial injected therein so as to release the active ingredient. Theporous matter may have an extremely large inert surface area, whichsurface area is available for binding. The recharging may compriseremoving carrier+therapeutic agent; and adding freshly “charged”carrier+therapeutic agent.

The elution may comprise a byproduct, for example unbound binding agentthat can be removed. For example, diffusion (plug flow) of vitreous tochange conditions, e.g. pH to reduce interaction of therapeuticagent+carriers.

Additionally or in the alternative, a sustained drug delivery system ofthe therapeutic agent may comprise drug delivery packets, e.g.microspheres, that are activated. The packets can be activated with atleast one of photochemical activation, thermal activation orbiodegradation.

The therapeutic device may comprise at least one structure configured toprovide safety precautions. The device may comprise at least onestructure to prevent at least one of macrophage or other immune cellwithin the reservoir body; bacterial penetration; or retinal detachment.

The therapeutic device may be configured for other applications in thebody. Other routes of administration of drugs may include at least oneof intraocular, oral, subcutaneous, intramuscular, intraperitoneal,intranasal, dermal, intrathecal, intravascular, intra articular,pericardial, intraluminal in organs and gut or the like.

Conditions that may be treated and/or prevented using the drug deliverydevice and method described herein may include at least one of thefollowing: hemophilia and other blood disorders, growth disorders,diabetes, leukemia, hepatitis, renal failure, HIV infection, hereditarydiseases such as cerebrosidase deficiency and adenosine deaminasedeficiency, hypertension, septic shock, autoimmune diseases such asmultiple sclerosis, Graves disease, systemic lupus erythematosus andrheumatoid arthritis, shock and wasting disorders, cystic fibrosis,lactose intolerance, Crohn's disease, inflammatory bowel disease,gastrointestinal or other cancers, degenerative diseases, trauma,multiple systemic conditions such as anemia, and ocular diseases suchas, for example, retinal detachment, proliferative retinopathy,proliferative diabetic retinopathy, degenerative disease, vasculardiseases, occlusions, infection caused by penetrating traumatic injury,endophthalmitis such as endogenous/systemic infection, post-operativeinfections, inflammations such as posterior uveitis, retinitis orchoroiditis and tumors such as neoplasms and retinoblastoma.

Examples of therapeutic agents 110 that may be delivered by thetherapeutic device 100 are described in Table 1A and may includeTriamcinolone acetonide, Bimatoprost (Lumigan), Ranibizumab (Lucentis™),Travoprost (Travatan, Alcon), Timolol (Timoptic, Merck), Levobunalol(Betagan, Allergan), Brimonidine (Alphagan, Allergan), Dorzolamide(Trusopt, Merck), Brinzolamide (Azopt, Alcon). Additional examples oftherapeutic agents that may be delivered by the therapeutic deviceinclude antibiotics such as tetracycline, chlortetracycline, bacitracin,neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline,chloramphenicol kanamycin, rifampicin, ciprofloxacin, tobramycin,gentamycin, erythromycin and penicillin; antifungals such asamphotericin B and miconazole; anti-bacterials such as sulfonamides,sulfadiazine, sulfacetamide, sulfamethizole and sulfisoxazole,nitrofurazone and sodium propionate; antivirals such as idoxuridine,trifluorotymidine, acyclovir, ganciclovir and interferon;antiallergenics such as sodium cromoglycate, antazoline, methapyriline,chlorpheniramine, pyrilamine, cetirizine and prophenpyridamine;anti-inflammatories such as hydrocortisone, hydrocortisone acetate,dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone,prednisolone, prednisolone 21-phosphate, prednisolone acetate,fluoromethalone, betamethasone, and triamcinolone; non-steroidalanti-inflammatories such as salicylate, indomethacin, ibuprofen,diclofenac, flurbiprofen and piroxicam; decongestants such asphenylephrine, naphazoline and tetrahydrozoline; miotics andanticholinesterases such as pilocarpine, salicylate, acetylcholinechloride, physostigmine, eserine, carbachol, diisopropylfluorophosphate, phospholine iodide and demecarium bromide; mydriaticssuch as atropine sulfate, cyclopentolate, homatropine, scopolamine,tropicamide, eucatropine and hydroxyamphetamine; sypathomimetics such asepinephrine; antineoplastics such as carmustine, cisplatin andfluorouracil; immunological drugs such as vaccines and immunestimulants; hormonal agents such as estrogens, estradiol,progestational, progesterone, insulin, calcitonin, parathyroid hormoneand peptide and vasopressin hypothalamus releasing factor; betaadrenergic blockers such as timolol maleate, levobunolol Hcl andbetaxolol Hcl; growth factors such as epidermal growth factor,fibroblast growth factor, platelet derived growth factor, transforminggrowth factor beta, somatotropin and fibronectin; carbonic anhydraseinhibitors such as dichlorophenamide, acetazolamide and methazolamideand other drugs such as prostaglandins, antiprostaglandins andprostaglandin precursors. Other therapeutic agents known to thoseskilled in the art which are capable of controlled, sustained releaseinto the eye in the manner described herein are also suitable for use inaccordance with embodiments of the present invention.

The therapeutic agent 110 may comprise one or more of the following:Abarelix, Abatacept, Abciximab, Adalimumab, Aldesleukin, Alefacept,Alemtuzumab, Alpha-1-proteinase inhibitor, Alteplase, Anakinra,Anistreplase, Antihemophilic Factor, Antithymocyte globulin, Aprotinin,Arcitumomab, Asparaginase, Basiliximab, Becaplermin, Bevacizumab,Bivalirudin, Botulinum Toxin Type A, Botulinum Toxin Type B, Capromab,Cetrorelix, Cetuximab, Choriogonadotropin alfa, Coagulation Factor IX,Coagulation factor VIIa, Collagenase, Corticotropin, Cosyntropin,Cyclosporine, Daclizumab, Darbepoetin alfa, Defibrotide, Denileukindiftitox, Desmopressin, Dornase Alfa, Drotrecogin alfa, Eculizumab,Efalizumab, Enfuvirtide, Epoetin alfa, Eptifibatide, Etanercept,Exenatide, Felypressin, Filgrastim, Follitropin beta, Galsulfase,Gemtuzumab ozogamicin, Glatiramer Acetate, Glucagon recombinant,Goserelin, Human Serum Albumin, Hyaluronidase, Ibritumomab, Idursulfase,Immune globulin, Infliximab, Insulin Glargine recombinant, InsulinLyspro recombinant, Insulin recombinant, Insulin, porcine, InterferonAlfa-2a, Recombinant, Interferon Alfa-2b, Recombinant, Interferonalfacon-1, Interferonalfa-n1, Interferon alfa-n3, Interferon beta-1b,Interferon gamma-1b, Lepirudin, Leuprolide, Lutropin alfa, Mecasermin,Menotropins, Muromonab, Natalizumab, Nesiritide, Octreotide, Omalizumab,Oprelvekin, OspA lipoprotein, Oxytocin, Palifermin, Palivizumab,Panitumumab, Pegademase bovine, Pegaptanib, Pegaspargase, Pegfilgrastim,Peginterferon alfa-2a, Peginterferon alfa-2b, Pegvisomant, Pramlintide,Ranibizumab, Rasburicase, Reteplase, Rituximab, Salmon Calcitonin,Sargramostim, Secretin, Sermorelin, Serum albumin iodonated, Somatropinrecombinant, Streptokinase, Tenecteplase, Teriparatide, ThyrotropinAlfa, Tositumomab, Trastuzumab, Urofollitropin, Urokinase, orVasopressin. The molecular weights of the molecules and indications ofthese therapeutic agents are set for below in Table 1A, below.

The therapeutic agent 110 may comprise one or more of compounds that actby binding members of the immunophilin family of cellular proteins. Suchcompounds are known as “immunophilin binding compounds.” Immunophilinbinding compounds include but are not limited to the “limus” family ofcompounds. Examples of limus compounds that may be used include but arenot limited to cyclophilins and FK506-binding proteins (FKBPs),including sirolimus (rapamycin) and its water soluble analog SDZ-RAD,tacrolimus, everolimus, pimecrolimus, CCI-779 (Wyeth), AP23841 (Ariad),and ABT-578 (Abbott Laboratories).

The limus family of compounds may be used in the compositions, devicesand methods for the treatment, prevention, inhibition, delaying theonset of, or causing the regression of angiogenesis-mediated diseasesand conditions of the eye, including choroidal neovascularization. Thelimus family of compounds may be used to prevent, treat, inhibit, delaythe onset of, or cause regression of AMD, including wet AMD. Rapamycinmay be used to prevent, treat, inhibit, delay the onset of, or causeregression of angiogenesis-mediated diseases and conditions of the eye,including choroidal neovascularization. Rapamycin may be used toprevent, treat, inhibit, delay the onset of, or cause regression of AMD,including wet AMD.

The therapeutic agent 110 may comprise one or more of: pyrrolidine,dithiocarbamate (NF.kappa.B inhibitor); squalamine; TPN 470 analogue andfumagillin; PKC (protein kinase C) inhibitors; Tie-1 and Tie-2 kinaseinhibitors; inhibitors of VEGF receptor kinase; proteosome inhibitorssuch as Velcade™ (bortezomib, for injection; ranibuzumab (Lucentis™) andother antibodies directed to the same target; pegaptanib (Macugen™);vitronectin receptor antagonists, such as cyclic peptide antagonists ofvitronectin receptor-type integrins; .alpha.-v/.beta.-3 integrinantagonists; .alpha.-v/.beta.-1 integrin antagonists; thiazolidinedionessuch as rosiglitazone or troglitazone; interferon, including.gamma.-interferon or interferon targeted to CNV by use of dextran andmetal coordination; pigment epithelium derived factor (PEDF);endostatin; angiostatin; tumistatin; canstatin; anecortave acetate;acetonide; triamcinolone; tetrathiomolybdate; RNA silencing or RNAinterference (RNAi) of angiogenic factors, including ribozymes thattarget VEGF expression; Accutane™ (13-cis retinoic acid); ACEinhibitors, including but not limited to quinopril, captopril, andperindozril; inhibitors of mTOR (mammalian target of rapamycin);3-aminothalidomide; pentoxifylline; 2-methoxyestradiol; colchicines;AMG-1470; cyclooxygenase inhibitors such as nepafenac, rofecoxib,diclofenac, rofecoxib, NS398, celecoxib, vioxx, and(E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA synthasemodulator; metalloprotease 13 inhibitor; acetylcholinesterase inhibitor;potassium channel blockers; endorepellin; purine analog of6-thioguanine; cyclic peroxide ANO-2; (recombinant) arginine deiminase;epigallocatechin-3-gallate; cerivastatin; analogues of suramin; VEGFtrap molecules; apoptosis inhibiting agents; Visudyne™, snET2 and otherphoto sensitizers, which may be used with photodynamic therapy (PDT);inhibitors of hepatocyte growth factor (antibodies to the growth factoror its receptors, small molecular inhibitors of the c-met tyrosinekinase, truncated versions of HGF e.g. NK4).

The therapeutic agent 110 may comprise a combination with othertherapeutic agents and therapies, including but not limited to agentsand therapies useful for the treatment of angiogenesis orneovascularization, particularly CNV. Non-limiting examples of suchadditional agents and therapies include pyrrolidine, dithiocarbamate(NF.kappa.B inhibitor); squalamine; TPN 470 analogue and fumagillin; PKC(protein kinase C) inhibitors; Tie-1 and Tie-2 kinase inhibitors;inhibitors of VEGF receptor kinase; proteosome inhibitors such asVelcade™ (bortezomib, for injection; ranibuzumab (Lucentis™) and otherantibodies directed to the same target; pegaptanib (Macugen™);vitronectin receptor antagonists, such as cyclic peptide antagonists ofvitronectin receptor-type integrins; .alpha.-v/.beta.-3 integrinantagonists; .alpha.-v/.beta.-1 integrin antagonists; thiazolidinedionessuch as rosiglitazone or troglitazone; interferon, including.gamma.-interferon or interferon targeted to CNV by use of dextran andmetal coordination; pigment epithelium derived factor (PEDF);endostatin; angiostatin; tumistatin; canstatin; anecortave acetate;acetonide; triamcinolone; tetrathiomolybdate; RNA silencing or RNAinterference (RNAi) of angiogenic factors, including ribozymes thattarget VEGF expression; Accutane™ (13-cis retinoic acid); ACEinhibitors, including but not limited to quinopril, captopril, andperindozril; inhibitors of mTOR (mammalian target of rapamycin);3-aminothalidomide; pentoxifylline; 2-methoxyestradiol; colchicines;AMG-1470; cyclooxygenase inhibitors such as nepafenac, rofecoxib,diclofenac, rofecoxib, NS398, celecoxib, vioxx, and(E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA synthasemodulator; metalloprotease 13 inhibitor; acetylcholinesterase inhibitor;potassium channel blockers; endorepellin; purine analog of6-thioguanine; cyclic peroxide ANO-2; (recombinant) arginine deiminase;epigallocatechin-3-gallate; cerivastatin; analogues of suramin; VEGFtrap molecules; inhibitors of hepatocyte growth factor (antibodies tothe growth factor or its receptors, small molecular inhibitors of thec-met tyrosine kinase, truncated versions of HGF e.g. NK4); apoptosisinhibiting agents; Visudyne™, snET2 and other photo sensitizers withphotodynamic therapy (PDT); and laser photocoagulation.

The therapeutic agents may be used in conjunction with apharmaceutically acceptable carrier such as, for example, solids such asstarch, gelatin, sugars, natural gums such as acacia, sodium alginateand carboxymethyl cellulose; polymers such as silicone rubber; liquidssuch as sterile water, saline, dextrose, dextrose in water or saline;condensation products of castor oil and ethylene oxide, liquid glyceryltriester of a lower molecular weight fatty acid; lower alkanols; oilssuch as corn oil, peanut oil, sesame oil, castor oil, and the like, withemulsifiers such as mono- or di-glyceride of a fatty acid, or aphosphatide such as lecithin, polysorbate 80, and the like; glycols andpolyalkylene glycols; aqueous media in the presence of a suspendingagent, for example, sodium carboxymethylcellulose, sodium hyaluronate,sodium alginate, poly(vinyl pyrrolidone) and similar compounds, eitheralone, or with suitable dispensing agents such as lecithin,polyoxyethylene stearate and the like. The carrier may also containadjuvants such as preserving, stabilizing, wetting, emulsifying agentsor other related materials.

The therapeutic device may comprise a container configured to hold atleast one therapeutic agent, the container comprising a chamber to holdthe at least one therapeutic agent with at least one opening to releasethe at least one therapeutic agent to the vitreous humor and porousstructure 150 placed within the at least one opening. The porousstructure 150 may comprise a fixed tortuous, porous material such as asintered metal, a sintered glass or a sintered polymer with a definedporosity and tortuosity that controls the rate of delivery of the atleast one therapeutic agent to the vitreous humor. The rigid porousstructures provide certain advantages over capillary tubes, erodiblepolymers and membranes as a mechanism for controlling the release of atherapeutic agent or agents from the therapeutic device. Theseadvantages include the ability of the rigid porous structure to comprisea needle stop, simpler and more cost effective manufacture, flushabilityfor cleaning or declogging either prior to or after implantation, highefficiency depth filtration of microorganisms provided by the labyrinthsof irregular paths within the structure and greater robustness due togreater hardness and thickness of the structure compared to a membraneor erodible polymer matrix. Additionally, when the rigid porousstructure is manufactured from a sintered metal, ceramic, glass orcertain plastics, it can be subjected to sterilization and cleaningprocedures, such as heat or radiation based sterilization anddepyrogenation, that might damage polymer and other membranes. Incertain embodiments, as illustrated in example 9, the rigid porousstructure may be configured to provide a therapeutically effective,concentration of the therapeutic agent in the vitreous for at least 6months. This release profile provided by certain configurations of therigid porous structures enables a smaller device which is preferred in asmall organ such as the eye where larger devices may alter or impairvision.

FIG. 6A1 shows a therapeutic device 100 comprising a container 130having a penetrable barrier 184 disposed on a first end, a porousstructure 150 disposed on a second end to release therapeutic agent foran extended period, and a retention structure 120 comprising anextension protruding outward from the container to couple to the scleraand the conjunctiva. The extending protrusion of the retention structuremay comprise a diameter 120D. The retention structure may comprise anindentation 1201 sized to receive the sclera. The container may comprisea tubular barrier 160 that defines at least a portion of the reservoir,and the container may comprise a width, for example a diameter 134. Thediameter 134 can be sized within a range, for example within a rangefrom about 0.5 to about 4 mm, for example within a range from about 1 to3 mm and can be about 2 mm, for example. The container may comprise alength 136, sized so as to extend from the conjunctive to the vitreousto release the therapeutic agent into the vitreous. The length 136 canbe sized within a range, for example within a range from about 0.2 toabout 14 mm, for example within a range from about 4 to 10 mm and can beabout 7 mm, for example. The volume of the reservoir may besubstantially determined by an inner cross sectional area of the tubularstructure and distance from the porous structure to the penetrablebarrier. The retention structure may comprise an annular extensionhaving a retention structure diameter greater than a diameter of thecontainer. The retention structure may comprise an indentationconfigured to receive the sclera when the extension extends between thesclera and the conjunctive. The penetrable barrier may comprise a septumdisposed on a proximal end of the container, in which the septumcomprises a barrier that can be penetrated with a sharp object such as aneedle for injection of the therapeutic agent. The porous structure maycomprise a cross sectional area 150A sized to release the therapeuticagent for the extended period.

The porous structure 150 may comprise a first side coupled to thereservoir 150S1 and a second side to couple to the vitreous 150S2. Thefirst side may comprise a first area 150A1 and the second side maycomprise a second area 150A2. The porous structure may comprise athickness 105T. The porous structure many comprise a diameter 150D.

The volume of the reservoir 140 may comprise from about 5 uL to about2000 uL of therapeutic agent, or for example from about 10 uL to about200 uL of therapeutic agent.

The therapeutic agent stored in the reservoir of the container comprisesat least one of a solid comprising the therapeutic agent, a solutioncomprising the therapeutic agent, a suspension comprising thetherapeutic agent, particles comprising the therapeutic agent adsorbedthereon, or particles reversibly bound to the therapeutic agent. Forexample, reservoir may comprise a suspension of a cortico-steroid suchas triamcinolone acetonide to treat inflammation of the retina. Thereservoir may comprise a buffer and a suspension of a therapeutic agentcomprising solubility within a range from about 1 ug/mL to about 100ug/mL, such as from about 1 ug/mL to about 40 ug/mL. For example, thetherapeutic agent may comprise a suspension of triamcinolone acetonidehaving a solubility of approximately 19 ug/mL in the buffer at 37° C.when implanted.

The release rate index may comprise many values, and the release rateindex with the suspension may be somewhat higher than for a solution inmany embodiments, for example. The release rate index may be no morethan about 5, and can be no more than about 2.0, for example no morethan about 1.5, and in many embodiments may be no more than about 1.2,so as to release the therapeutic agent with therapeutic amounts for theextended time.

The therapeutic device, including for example, the retention structureand the porous structure, may be sized to pass through a lumen of acatheter.

The porous structure may comprise a needle stop that limits penetrationof the needle. The porous structure may comprise a plurality of channelsconfigured for the extended release of the therapeutic agent. The porousstructure may comprise a rigid sintered material having characteristicssuitable for the sustained release of the material.

FIG. 6A2 shows a therapeutic device as in FIG. 6A comprising a roundeddistal end.

FIG. 6B shows a rigid porous structure as in FIG. 6A. The rigid porousstructure 158 comprises a plurality of interconnecting channels 156. Theporous structure comprises a sintered material composed ofinterconnected grains 155 of material. The interconnected grains ofmaterial define channels that extend through the porous material torelease the therapeutic agent. The channels may extend around thesintered grains of material, such that the channels compriseinterconnecting channels extending through the porous material.

The rigid porous structure can be configured for injection of thetherapeutic agent into the container in many ways. The channels of therigid porous structure may comprise substantially fixed channels whenthe therapeutic agent is injected into the reservoir with pressure. Therigid porous structure comprises a hardness parameter within a rangefrom about 160 Vickers to about 500 Vickers. In some embodiments therigid porous structure is formed from sintered stainless steel andcomprises a hardness parameter within a range from about 200 Vickers toabout 240 Vickers. In some embodiments it is preferred to inhibitejection of the therapeutic agent through the porous structure duringfilling or refilling the reservoir of the therapeutic device with afluid. In these embodiments the channels of the rigid porous structurecomprise a resistance to flow of an injected solution or suspensionthrough a thirty gauge needle such that ejection of said solution orsuspension through the rigid porous structure is substantially inhibitedwhen said solution or suspension is injected into the reservoir of thetherapeutic device. Additionally, these embodiments may optionallycomprise an evacuation vent or an evacuation reservoir under vacuum orboth to facilitate filling or refilling of the reservoir.

The reservoir and the porous structure can be configured to releasetherapeutic amounts of the therapeutic agent in many ways. The reservoirand the porous structure can be configured to release therapeuticamounts of the therapeutic agent corresponding to a concentration of atleast about 0.1 ug per ml of vitreous humor for an extended period of atleast about three months. The reservoir and the porous structure can beconfigured to release therapeutic amounts of the therapeutic agentcorresponding to a concentration of at least about 0.1 ug per ml ofvitreous humor and no more than about 10 ug per ml for an extendedperiod of at least about three months. The therapeutic agent maycomprise at least a fragment of an antibody and a molecular weight of atleast about 10 k Daltons. For example, the therapeutic agent maycomprise one or more of ranibizumab or bevacizumab. Alternatively or incombination, the therapeutic agent may comprise a small molecule drugsuitable for sustained release. The reservoir and the porous structuremay be configured to release therapeutic amounts of the therapeuticagent corresponding to a concentration of at least about 0.1 ug per mlof vitreous humor and no more than about 10 ug per ml for an extendedperiod of at least about 3 months or at least about 6 months. Thereservoir and the porous structure can be configured to releasetherapeutic amounts of the therapeutic agent corresponding to aconcentration of at least about 0.1 ug per ml of vitreous humor and nomore than about 10 ug per ml for an extended period of at least abouttwelve months or at least about two years or at least about three years.The reservoir and the porous structure may also be configured to releasetherapeutic amounts of the therapeutic agent corresponding to aconcentration of at least about 0.01 ug per ml of vitreous humor and nomore than about 300 ug per ml for an extended period of at least about 3months or 6 months or 12 months or 24 months.

The channels of the rigid porous structure comprise a hydrogelconfigured to limit a size of molecules passed through the channels ofthe rigid porous structure. For example, the hydrogel can be formedwithin the channels and may comprise an acrylamide gel. The hydrogelcomprises a water content of at least about 70%. For example, thehydrogel may comprise a water content of no more than about 90% to limitmolecular weight of the therapeutic agent to about 30 k Daltons. Thehydrogel comprises a water content of no more than about 95% to limitmolecular weight of the therapeutic agent to about 100 k Daltons. Thehydrogel may comprise a water content within a range from about 90% toabout 95% such that the channels of the porous material are configuredto pass Lucentis™ and substantially not pass Avastin™

The rigid porous structure may comprise a composite porous material thatcan readily be formed in or into a wide range of different shapes andconfigurations. For example, the porous material can be a composite of ametal, aerogel or ceramic foam (i.e., a reticulated inter-cellularstructure in which the interior cells are interconnected to provide amultiplicity of pores passing through the volume of the structure, thewalls of the cells themselves being substantially continuous andnon-porous, and the volume of the cells relative to that of the materialforming the cell walls being such that the overall density of theintercellular structure is less than about 30 percent theoreticaldensity) the through pores of which are impregnated with a sinteredpowder or aerogel. The thickness, density, porosity and porouscharacteristics of the final composite porous material can be varied toconform with the desired release of the therapeutic agent.

Embodiments comprise a method of making an integral (i.e.,single-component) porous structure. The method may comprise introducingparticles into a mold having a desired shape for the porous structure.The shape includes a proximal end defining a plurality of proximalporous channel openings to couple to the reservoir, a distal enddefining a plurality of outlet channel openings to couple to thevitreous humor of the eye, a plurality of blind inlet cavities extendinginto the filter from the proximal openings, and a plurality of blindoutlet cavities extending into the porous structure from the outletchannel openings. The method further includes applying pressure to themold, thereby causing the particles to cohere and form a singlecomponent, and sintering the component to form the porous structure. Theparticles can be pressed and cohere to form the component without theuse of a polymeric binder, and the porous structure can be formedsubstantially without machining.

The mold can be oriented vertically with the open other end disposedupwardly, and metal powder having a particle size of less than 20micrometers can be introduced into the cavity through the open end ofthe mold while vibrating the mold to achieve substantially uniformpacking of the metal powder in the cavity. A cap can be placed on theopen other end of the mold, and pressure is applied to the mold andthereby to the metal powder in the cavity to cause the metal powder tocohere and form a cup-shaped powdered metal structure having a shapecorresponding to the mold. The shaped powdered metal structure can beremoved from the mold, and sintered to obtain a porous sintered metalporous structure.

The metal porous structure can be incorporated into the device by apress fit into an impermeable structure with an opening configured toprovide a tight fit with the porous structure. Other means, such aswelding, known to those skilled in the art can be used to incorporatethe porous structure into the device. Alternatively, or in combination,the powdered metal structure can be formed in a mold where a portion ofthe mold remains with the shaped powdered metal structure and becomespart of the device. This may be advantageous in achieving a good sealbetween the porous structure and the device.

The release rate of therapeutic agent through a porous body, such as asintered porous metal structure or a porous glass structure, may bedescribed by diffusion of the of the therapeutic agent within the porousstructure with the channel parameter, and with an effective diffusioncoefficient equal to the diffusion coefficient of the therapeutic agentin the liquid that fills the reservoir multiplied by the Porosity and aChannel Parameter of the porous body:

Release Rate=(D P/F) A (c_(R)−c_(V))/L, where:c_(R)=Concentration in reservoirc_(V)=Concentration outside of the reservoir or in the vitreousD=Diffusion coefficient of the therapeutic agent in the reservoirsolutionP=Porosity of porous structureF=Channel parameter that may correspond to a tortuosity parameter ofchannels of porous structureA=Area of porous structureL=Thickness (length) of porous structureCumulative Release=1−cR/cR0=1−exp ((−D PA/FL V_(R))t), wheret=time, Vr=reservoir volume

The release rate index can (hereinafter RRI) be used to determinerelease of the therapeutic agent. The RRI may be defined as (PA/FL), andthe RRI values herein will have units of mm unless otherwise indicated.Many of the porous structures used in the therapeutic delivery devicesdescribed here have an RRI of no more than about 5.0, often no more thanabout 2.0, and can be no more than about 1.2 mm.

The channel parameter can correspond to an elongation of the path of thetherapeutic agent released through the porous structure. The porousstructure may comprise many interconnecting channels, and the channelparameter can correspond to an effective length that the therapeuticagent travels along the interconnecting channels of the porous structurefrom the reservoir side to the vitreous side when released. The channelparameter multiplied by the thickness (length) of the porous structurecan determine the effective length that the therapeutic agent travelsalong the interconnecting channels from the reservoir side to thevitreous side. For example, the channel parameter (F) of about 1.5corresponds to interconnecting channels that provide an effectiveincrease in length traveled by the therapeutic agent of about 50%, andfor a 1 mm thick porous structure the effective length that thetherapeutic agent travels along the interconnecting channels from thereservoir side to the vitreous side corresponds to about 1.5 mm. Thechannel parameter (F) of at least about 2 corresponds to interconnectingchannels that provide an effective increase in length traveled by thetherapeutic agent of about 100%, and for a 1 mm thick porous structurethe effective length that the therapeutic agent travels along theinterconnecting channels from the reservoir side to the vitreous sidecorresponds to at least about 2.0 mm. As the porous structure comprisesmany interconnecting channels that provide many alternative paths forrelease of the therapeutic agent, blockage of some of the channelsprovides no substantial change in the effective path length through theporous structure as the alternative interconnecting channels areavailable, such that the rate of diffusion through the porous structureand the release of the therapeutic agent are substantially maintainedwhen some of the channels are blocked.

If the reservoir solution is aqueous or has a viscosity similar towater, the value for the diffusion coefficient of the therapeutic agent(TA) in water at the temperature of interest may be used. The followingequation can be used to estimate the diffusion coefficient at 37° C.from the measured value of D_(BSA,20C)=6.1 e−7 cm2/s for bovine serumalbumin in water at 20° C. (Molokhia et al, Exp Eye Res 2008):

D _(TA,37C) =D _(BSA,20C)(η_(20C)/η_(37C))(MW _(BSA) /MW _(TA))^(1/3)where

MW refers to the molecular weight of either BSA or the test compound andη is the viscosity of water. The following lists diffusion coefficientsof proteins of interest.

Temp Diff Coeff Compound MW C. (cm{circumflex over ( )}2/s) BSA 69,00020 6.1E−07 BSA 69,000 37 9.1E−07 Ranibizumab 48,000 20 6.9E−07Ranibizumab 48,000 37 1.0E−06 Bevacizumab 149,000 20 4.7E−07 Bevacizumab149,000 37 7.1E−07

Small molecules have a diffusion coefficient similar to fluorescein(MW=330, D=4.8 to 6 e−6 cm²/s from Stay, M S et al. Pharm Res 2003,20(1), pp. 96-102). For example, the small molecule may comprise aglucocorticoid such as triamcinolone acetonide having a molecular weightof about 435.

The porous structure comprises a porosity, a thickness, a channelparameter and a surface area configured to release therapeutic amountsfor the extended period. The porous material may comprise a porositycorresponding to the fraction of void space of the channels extendingwithin the material. The porosity comprises a value within a range fromabout 3% to about 70%. In other embodiments, the porosity comprises avalue with a range from about 5% to about 10% or from about 10% to about25%, or for example from about 15% to about 20%. Porosity can bedetermined from the weight and macroscopic volume or can be measured vianitrogen gas adsorption

The porous structure may comprise a plurality of porous structures, andthe area used in the above equation may comprise the combined area ofthe plurality of porous structures.

The channel parameter may comprise a fit parameter corresponding to thetortuosity of the channels. For a known porosity, surface area andthickness of the surface parameter, the curve fit parameter F, which maycorrespond to tortuosity of the channels can be determined based onexperimental measurements. The parameter PA/FL can be used to determinethe desired sustained release profile, and the values of P, A, F and Ldetermined. The rate of release of the therapeutic agent corresponds toa ratio of the porosity to the channel parameter, and the ratio of theporosity to the channel parameter can be less than about 0.5 such thatthe porous structure releases the therapeutic agent for the extendedperiod. For example, the ratio of the porosity to the channel parameteris less than about 0.1 or for example less than about 0.2 such that theporous structure releases the therapeutic agent for the extended period.The channel parameter may comprise a value of at least about 1, such asat least about 1.2. For example, the value of the channel parameter maycomprise at least about 1.5, for example at least about 2, and maycomprise at least about 5. The channel parameter can be within a rangefrom about 1.1 to about 10, for example within a range from about 1.2 toabout 5. A person of ordinary skill in the art can conduct experimentsbased on the teachings described herein to determine empirically thechannel parameter to release the therapeutic agent for an intendedrelease rate profile.

The area in the model originates from the description of masstransported in units of flux; i.e., rate of mass transfer per unit area.For simple geometries, such as a porous disc mounted in an impermeablesleeve of equal thickness, the area corresponds to one face of the discand the thickness, L, is the thickness of the disc. For more complexgeometries, such as a porous body in the shape of a truncated cone, theeffective area is a value in between the area where therapeutic agententers the porous body and the area where therapeutic agent exits theporous body.

A model can be derived to describe the release rate as a function oftime by relating the change of concentration in the reservoir to therelease rate described above. This model assumes a solution oftherapeutic agent where the concentration in the reservoir is uniform.In addition, the concentration in the receiving fluid or vitreous isconsidered negligible (c_(V)=0). Solving the differential equation andrearrangement yields the following equations describing theconcentration in the reservoir as a function of time, t, and volume ofthe reservoir, V_(R), for release of a therapeutic agent from a solutionin a reservoir though a porous structure.

c _(R) =c _(R0)exp((−D PA/FL V _(R))t)

and Cumulative Release=1−c_(R)/C_(R0)

When the reservoir contains a suspension, the concentration inreservoir, c_(R), is the dissolved concentration in equilibrium with thesolid (i.e., the solubility of the therapeutic agent). In this case, theconcentration in the reservoir is constant with time, the release rateis zero order, and the cumulative release increases linearly with timeuntil the time when the solid is exhausted.

Therapeutic concentrations for many ophthalmic therapeutic agents may bedetermined experimentally by measuring concentrations in the vitreoushumor that elicit a therapeutic effect. Therefore, there is value inextending predictions of release rates to predictions of concentrationsin the vitreous. A one-compartment model may be used to describeelimination of therapeutic agent from eye tissue.

Current intravitreal administration of therapeutic agents such asLucentis™ involves a bolus injection. A bolus injection into thevitreous may be modeled as a single exponential with rate constant,k=0.693/half-life and a cmax=dose/V_(v) where V_(v) is the vitreousvolume. As an example, the half-life for ranibizumab is approximately 3days in the rabbit and the monkey (Gaudreault et al.) and 9 days inhumans (Lucentis™ package insert). The vitreous volume is approximately1.5 mL for the rabbit and monkey and 4.5 mL for the human eye. The modelpredicts an initial concentration of 333 ug/mL for a bolus injection of0.5 mg Lucentis™ into the eye of a monkey. This concentration decays toa vitreous concentration of 0.1 ug/mL after about a month.

For devices with extended release, the concentration in the vitreouschanges slowly with time. In this situation, a model can be derived froma mass balance equating the release rate from the device (described byequations above) with the elimination rate from the eye, k c_(v) V_(v).Rearrangement yields the following equation for the concentration in thevitreous:

c _(v)=Release rate from device/k V _(v).

Since the release rate from a device with a solution of therapeuticagent decreases exponentially with time, the concentration in thevitreous decreases exponentially with the same rate constant. In otherwords, vitreous concentration decreases with a rate constant equal to DPA/FL Y_(R) and, hence, is dependent on the properties of the porousstructure and the volume of the reservoir.

Since the release rate is zero order from a device with a suspension oftherapeutic agent, the vitreous concentration will also betime-independent. The release rate will depend on the properties of theporous structure via the ratio, PA/FL, but will be independent of thevolume of the reservoir until the time at which the drug is exhausted.

The channels of the rigid porous structure can be sized in many ways torelease the intended therapeutic agent. For example, the channels of therigid porous structure can be sized to pass therapeutic agent comprisingmolecules having a molecular weight of at least about 100 Daltons or forexample, at least about 50 k Daltons. The channels of the rigid porousstructure can be sized to pass therapeutic agent comprising moleculescomprising a cross-sectional size of no more than about 10 nm. Thechannels of the rigid porous structure comprise interconnecting channelsconfigured to pass the therapeutic agent among the interconnectingchannels. The rigid porous structure comprises grains of rigid materialand wherein the interconnecting channels extend at least partiallyaround the grains of rigid material to pass the therapeutic agentthrough the porous material. The grains of rigid material can be coupledtogether at a loci of attachment and wherein the interconnectingchannels extend at least partially around the loci of attachment.

The porous structure and reservoir may be configured to release theglucocorticoid for an extended time of at least about six months with atherapeutic amount of glucocorticoid of corresponding to an in situconcentration within a range from about 0.05 ug/mL to about 4 ug/mL, forexample from 0.1 ug/mL to about 4 ug/mL, so as to suppress inflammationin the retina-choroid.

The porous structure comprises a sintered material. The sinteredmaterial may comprise grains of material in which the grains comprise anaverage size of no more than about 20 um. For example, the sinteredmaterial may comprise grains of material in which the grains comprise anaverage size of no more than about 10 um, an average size of no morethan about 5 um, or an average size of no more than about 1 um. Thechannels are sized to pass therapeutic quantities of the therapeuticagent through the sintered material for the extended time based on thegrain size of the sintered material and processing parameters such ascompaction force and time and temperature in the furnace. The channelscan be sized to inhibit penetration of microbes including bacteria andfungal spores through the sintered material.

The sintered material comprises a wettable material to inhibit bubbleswithin the channels of the material.

The sintered material comprises at least one of a metal, a ceramic, aglass or a plastic. The sintered material may comprises a sinteredcomposite material, and the composite material comprises two or more ofthe metal, the ceramic, the glass or the plastic. The metal comprises atleast one of Ni, Ti, nitinol, stainless steel including alloys such as304, 304L, 316 or 316L, cobalt chrome, elgiloy, hastealloy, c-276 alloyor Nickel 200 alloy. The sintered material may comprise a ceramic. Thesintered material may comprise a glass. The plastic may comprise awettable coating to inhibit bubble formation in the channels, and theplastic may comprise at least one of polyether ether ketone (PEEK),polyethylene, polypropylene, polyimide, polystyrene, polycarbonate,polyacrylate, polymethacrylate, or polyamide.

The rigid porous structure may comprise a plurality of rigid porousstructures coupled to the reservoir and configured to release thetherapeutic agent for the extended period. For example, additional rigidporous structure can be disposed along the container, for example theend of the container may comprise the porous structure, and anadditional porous structure can be disposed along a distal portion ofthe container, for example along a tubular sidewall of the container.

The therapeutic device can be tuned to release therapeutic amounts ofthe therapeutic agent above the minimum inhibitory concentration for anextended time based on bolus injections of the therapeutic agent. Forexample, the volume of the chamber of the reservoir can be sized withthe release rate of the porous structure based on the volume of thebolus injection. A formulation of a therapeutic agent can be provided,for example a known intravitreal injection formulation. The therapeuticagent can be capable of treating the eye with bolus injections, suchthat the formulation has a corresponding period between each of thebolus injections to treat the eye. For example the bolus injections maycomprise monthly injections. Each of the bolus injections comprises avolume of the formulation, for example 50 uL. Each of the bolusinjections of the therapeutic agent may correspond to a range oftherapeutic concentrations of the therapeutic agent within the vitreoushumor over the time course between injections, and the device can betuned so as to release therapeutic amounts of the therapeutic agent suchthat the vitreous concentrations of the released therapeutic agent fromthe device are within the range of therapeutic concentrations of thecorresponding bolus injections. For example, the therapeutic agent maycomprise a minimum inhibitory concentration to treat the eye, forexample at least about 3 ug/mL, and the values of the range oftherapeutic concentrations can be at least about 3 ug/mL. Thetherapeutic device can be configured to treat the eye with an injectionof the monthly volume of the formulation into the device, for examplethrough the penetrable barrier. The reservoir of the container has achamber to contain a volume of the therapeutic agent, for example 35 uL,and a mechanism to release the therapeutic agent from the chamber to thevitreous humor.

The volume of the container and the release mechanism can be tuned totreat the eye with the therapeutic agent with vitreous concentrationswithin the therapeutic range for an extended time with each injection ofthe quantity corresponding to the bolus injection, such that theconcentration of the therapeutic agent within the vitreous humor remainswithin the range of therapeutic concentrations and comprises at leastthe minimum inhibitory concentration. The extended time may comprise atleast about twice the corresponding period of the bolus injections. Therelease mechanism comprises one or more of a porous frit, a sinteredporous fit, a permeable membrane, a semi-permeable membrane, a capillarytube or a tortuous channel, nano-structures, nano-channels or sinterednano-particles. For example, the porous frit may comprises a porosity,cross sectional area, and a thickness to release the therapeutic agentfor the extended time. The volume of the container reservoir can besized in many ways in relation to the volume of the injected formulationand can be larger than the volume of injected formulation, smaller thanthe volume of injected formulation, or substantially the same as thevolume of injected formulation. For example, the volume of the containermay comprise no more than the volume of the formulation, such that atleast a portion of the formulation injected into the reservoir passesthrough the reservoir and comprises a bolus injection to treat thepatient immediately. As the volume of the reservoir is increased, theamount of formulation released to the eye through the porous structureupon injection can decrease along with the concentration of activeingredient of the therapeutic agent within the reservoir, and therelease rate index can be increased appropriately so as to providetherapeutic amounts of therapeutic agent for the extended time. Forexample, the volume of the reservoir of the container can be greaterthan the volume corresponding to the bolus injection, so as to providetherapeutic amounts for at least about five months, for example 6months, with an injection volume corresponding to a monthly injection ofLucentis™. For example, the formulation may comprise commerciallyavailable Lucentis™, 50 uL, and the reservoir may comprise a volume ofabout 100 uL and provide therapeutic vitreous concentrations of at leastabout 3 ug/mL for six months with 50 uL of Lucentis™ injected into thereservoir.

The chamber may comprise a substantially fixed volume and the releaserate mechanism comprises a substantially rigid structure to maintainrelease of the therapeutic agent above the minimum inhibitoryconcentration for the extended time with each injection of a pluralityof injections.

A first portion of the injection may pass through the release mechanismand treat the patient when the formulation is injected, and a secondportion of the formulation can be contained in the chamber when theformulation is injected.

FIG. 6B-1 shows interconnecting channels 156 extending from first side150S1 to second side 150S2 of the porous structure as in FIG. 6B. Theinterconnecting channels 156 extend to a first opening 158A1, a secondopening 158A2 and an Nth opening 158AN on the first side 150S1. Theinterconnecting channels 156 extend to a first opening 158B1, a secondopening 158B2 and an Nth opening 158BN on the second side 150S2. Each ofthe openings of the plurality of channels on the first side is connectedto each of the openings of plurality of channels on the second side,such that effective length traveled along the channels is greater thanthickness 150T. The channel parameter can be within a range from about1.1 to about 10, such that the effective length is within a range fromabout 1.1 to 10 times the thickness 150T. For example, the channelparameter can be about 1 and the porosity about 0.2, such that theeffective length corresponds to at least about 5 times the thickness150T.

FIG. 6B-2 shows a plurality of paths of the therapeutic agent along theinterconnecting channels extending from a first side 150S1 to a secondside 150S2 of the porous structure as in FIGS. 6B and 6B-1. Theplurality of paths comprises a first path 156P1 extending from the firstside to the second side, a second path 156P2 extending from the firstside to the second side and a third path 156P3 extending from the firstside to the second side, and many additional paths. The effect length ofeach of first path P1, second path P2 and third path P3 is substantiallysimilar, such that each opening on the first side can release thetherapeutic agent to each interconnected opening on the second side. Thesubstantially similar path length can be related to the sintered grainsof material and the channels that extend around the sintered material.The porous structure may comprise randomly oriented and connected grainsof material, packed beads of material, or combinations thereof. Thechannel parameter can be related to the structure of the sintered grainsof material and corresponding interconnecting channels, porosity of thematerial, and percolation threshold. Work in relation to embodimentsshows that the percolation threshold of the sintered grains may be belowthe porosity of the porous frit structure, such that the channels arehighly inter-connected. The sintered grains of material can provideinterconnected channels, and the grains can be selected to providedesired porosity and channel parameters and RRI as described herein.

The channel parameter and effective length from the first side to thesecond side can be configured in many ways. The channel parameter can begreater than 1 and within a range from about 1.2 to about 5.0, such thatthe effective length is within a range about 1.2 to 5.0 times thethickness 150T, although the channel parameter may be greater than 5,for example within a range from about 1.2 to 10. For example, thechannel parameter can be from about 1.3 to about 2.0, such that theeffective length is about 1.3 to 2.0 times the thickness 150T. Forexample, experimental testing has shown the channel parameter can befrom about 1.4 to about 1.8, such that the effective length is about 1.4to 1.8 times the thickness 150T, for example about 1.6 times thethickness. These values correspond to the paths of the channels aroundthe sintered grains of material, and may correspond, for example, to thepaths of channels around packed beads of material.

FIG. 6B-3 shows blockage of the openings with a covering 156B and theplurality of paths of the therapeutic agent along the interconnectingchannels extending from a first side to a second side of the porousstructure as in FIGS. 6B and 6B-1. A plurality of paths 156PR extendfrom the first side to the second side couple the first side to thesecond side where one of the sides is covered, such that the flow rateis maintained when one of the sides is partially covered.

FIG. 6B-4 shows blockage of the openings with particles 156PB and theplurality of paths of the therapeutic agent along the interconnectingchannels extending from a first side to a second side of the porousstructure as in FIGS. 6B and 6B-1. The plurality of paths 156PR extendfrom the first side to the second side couple the first side to thesecond side where one of the sides is covered, such that the flow rateis maintained when one of the sides is partially covered

FIG. 6B-5 shows an effective cross-sectional size 150DE and area 150EFFcorresponding to the plurality of paths of the therapeutic agent alongthe interconnecting channels extending from a first side to a secondside of the porous structure as in FIGS. 6B and 6B-1. The effectivecross sectional area of the interconnecting channels corresponds to theinternal cross-sectional area of the porous structure disposed betweenthe openings of the first side and the openings of the second side, suchthat the rate of release can be substantially maintained when thechannels are blocked on the first side and the second side.

The rigid porous structure can be shaped and molded in many ways forexample with tubular shapes, conical shapes, discs and hemisphericalshapes. The rigid porous structure may comprise a molded rigid porousstructure. The molded rigid porous structure may comprises at least oneof a disk, a helix or a tube coupled to the reservoir and configured torelease the therapeutic agent for the extended period.

FIG. 6C shows a rigid porous structure as in FIG. 6B incorporated into ascleral tack 601 as described in U.S. Pat. No. 5,466,233. The scleraltack comprises a head 602, a central portion 603 and a post 604. Thepost may comprise the reservoir 605 and the rigid porous structure 606as described above. The porous structure may comprise a molded conicalstructure having a sharp tip configured for insertion into the patient.Alternatively or in combination, the tip may be rounded.

FIG. 6E, shows a plurality of rigid porous structures as in FIG. 6Bincorporated with a drug delivery device for sustained release asdescribed in U.S. Pat. No. 5,972,369. The therapeutic device comprises areservoir 613 to contain the therapeutic agent and an impermeable andnon-porous outer surface 614. The reservoir is coupled to a rigid porousstructure 615 that extends to a distal end 617. The rigid porousstructure comprises an exposed area 616 on the distal end to release thetherapeutic agent, and the impermeable and non-porous outer surface mayextend to the distal end.

FIG. 6D shows a rigid porous structure as in FIG. 6B incorporated with adelivery device for sustained release as described in U.S. Pat. Pub.2003/0014036 A1. The drug delivery device comprises an inlet port 608 onthe proximal end and a hollow body 609 coupled to the inlet port. Thehollow body comprises many openings 612 that allow a solution injectedinto the inlet port to pass from the hollow body into a balloon 610. Theballoon comprises a distal end 611 disposed opposite the injection port.The balloon comprises a plurality of the rigid porous structures 607, asdescribed above. Each of the plurality of porous rigid structurescomprises a first surface exposed to the interior of the balloon and asecond surface configured to contact the vitreous. The calculated areacan be the combined area of the plurality of porous rigid structures asnoted above.

FIG. 6F shows a rigid porous structure as in FIG. 6B incorporated with anon-linear body member 618 for sustained release as described in U.S.Pat. No. 6,719,750. The non-linear member may comprise a helical shape.The non-linear member can be coupled to a cap 619 on the proximal end620. The non-linear member may comprise a lumen 621 filled withtherapeutic agent so as to comprise a reservoir 622. The porousstructure 623 can be disposed on a distal end 624 of the non-linearmember to release the therapeutic agent. The porous structure may belocated at additional or alternative locations of the non-linear member.For example a plurality of porous structures may be disposed along thenon-linear member at locations disposed between the cap and distal endso as to release therapeutic agent into the vitreous humor when the capis positioned against the sclera.

FIG. 6G shows porous nanostructures, in accordance with embodiments. Theporous structure 150 may comprise a plurality of elongate nano-channels156NC extending from a first side 150S1 of the porous structure to asecond side 150S2 of the porous structure. The porous structure 150 maycomprise a rigid material having the holes formed thereon, and the holesmay comprise a maximum dimension across such as a diameter. The diameterof the nano-channels may comprise a dimension across, for example fromabout 10 nm across, to about 1000 nm across, or larger. The channels maybe formed with etching of the material, for example lithographic etchingof the material. The channels may comprise substantially straightchannels such that the channel parameter F comprises about 1, and theparameters area A, and thickness or length L correspond to the combinedcross-sectional area of the channels and the thickness or length of theporous structure.

The porous structure 150 may comprise interconnecting nano-channels, forexample formed with a sintered nano-material. The sintered nanomaterialmay comprise nanoparticles sintered so as to form a plurality ofinterconnecting channels as described herein, and can be made of asuitable size so as to provide an RRI as described herein. For example,the porous structure 150 comprising interconnecting nano-channels maycomprise a decreased cross sectional area so as to provide a low RRI asdescribed herein, such as an RRI of about 0.001 or more, for example anRRI of 0.002. The area can be increased and thickness decreased of theporous structure 150 comprising interconnecting channels so as toprovide an increased RRI, for example of about 5. The RRI of the porousstructure 150 comprising the plurality of interconnecting channels maycomprise a value within a range from about 0.001 to about 5, for examplefrom about 0.002 to about 5, for example a sintered porous materialbased on the teachings described herein.

The injection of therapeutic agent into the device 100 as describedherein can be performed before implantation into the eye oralternatively when the therapeutic device is implanted into the eye.

FIG. 7 shows a therapeutic device 100 coupled to an injector 701 thatremoves material from the device and injects therapeutic agent 702 intothe device. The injector picks up spent media 703 and refills theinjector with fresh therapeutic agent. The therapeutic agent is injectedinto the therapeutic device. The spent media is pulled up into theinjector. The injector may comprise a stopper mechanism 704.

The injector 701 may comprise a first container 702C to contain aformulation of therapeutic agent 702 and a second container 703C toreceive the spent media 703. Work in relation to embodiments suggeststhat the removal of spent media 703 comprising material from thecontainer reservoir of the therapeutic device can remove particulatefrom the therapeutic device, for example particles comprised ofaggregated therapeutic agent such as protein. The needle 189 maycomprise a double lumen needle with a first lumen coupled to the firstcontainer and a second lumen coupled to the second container, such thatspent media 703 passes from the container reservoir of device 100 to theinjector. A valve 703V, for example a vent, can be disposed between thesecond lumen and the second container. When the valve is open andtherapeutic agent is injected, spent media 703 from the containerreservoir of the therapeutic device 100 passes to the second containerof the injector, such that at least a portion of the spent media withinthe therapeutic device is exchanged with the formulation. When the valveis closed and the therapeutic agent is injected, a portion of thetherapeutic agent passes from the reservoir of the therapeutic deviceinto the eye. For example, a first portion of formulation of therapeuticagent can be injected into therapeutic device 100 when the valve is opensuch that the first portion of the formulation is exchanged withmaterial disposed within the reservoir; the valve is then closed and asecond portion of the formulation is injected into therapeutic device100 such that at least a portion of the first portion passes through theporous structure into the eye. Alternatively or in combination, aportion of the second portion of injected formulation may pass throughthe porous structure when the second portion is injected into the eye.The second portion of formulation injected when the valve is closed maycorrespond to a volume of formulation that passes through the porousstructure into the vitreous humor to treat the patient immediately.

The needle 189 may comprise a dual lumen needle, for example asdescribed with reference to FIG. 7A2 shown below.

FIG. 7A shows a therapeutic device 100 coupled to an injector 701 toinject and remove material from the device. The injector may comprise atwo needle system configured to insert into a container of the device.The injector may simultaneously inject therapeutic agent through thefirst needle 705 (the injection needle) while withdrawing liquid fromthe device through the second needle 706 (the vent needle). Theinjection needle may be longer and/or have a smaller diameter than thevent needle to facilitate removal of prior material from the device. Thevent needle may also be attached to a vacuum to facilitate removal ofprior material from the device.

FIG. 7A-1 shows a therapeutic device 100 comprising a penetrable barriercoupled to an injector needle 189 comprising a stop 189S that positionsthe distal end of the needle near the proximal end of the reservoir 130of the device to flush the reservoir with ejection of liquid formulationthrough the porous fit structure, in accordance with embodiments. Forexample, the injector needle may comprise a single lumen needle having abevel that extends approximately 0.5 mm along the shaft of the needlefrom the tip of the needle to the annular portion of the needle. Thestop can be sized and positioned along an axis of the needle such thatthe needle tip extends a stop distance 189SD into the reservoir asdefined by the length of the needle from the stop to the tip and thethickness of the penetrable barrier, in which the stop distance iswithin a range from about 0.5 to about 2 mm. The reservoir may extendalong an axis of the therapeutic device distance within a range fromabout 4 to 8 mm. A volume comprising a quantity of liquid formulationwithin a range from about 20 to about 200 uL, for example about 50 uLcan be injected into the therapeutic device with the needle tip disposedon the distal end. The volume of the reservoir can be less than theinjection volume of the formulation of therapeutic agent, such thatliquid is flushed through the porous structure 150. For example, thereservoir may comprise a volume within a range from about 20 to 40 uL,and the injection volume of the liquid formulation of therapeutic agentmay comprise about 40 to 100 uL, for example about 50 uL.

FIG. 7A-2 shows a therapeutic device comprising a penetrable barriercoupled to a needle 189 of an injector 701 to inject and remove materialfrom the device such that the liquid in the reservoir 130 is exchangedwith the injected formulation. The needle comprises at least one lumenand may comprise a concentric double lumen needle 189DL with a distalend coupled to the inner lumen to inject formulation of the therapeuticagent into the therapeutic device and a proximal vent 189V to receiveliquid into the needle when the formulation is injected. Alternatively,the vent may correspond to an opening on the distal end of the innerlumen of the needle and the outer lumen may comprise a proximal openingto inject therapeutic agent formulation into a proximal portion of thecontainer reservoir.

Work in relation to the injector embodiments indicates that a fillingefficiency of at least about 80%, for example 90% or more can beachieved with injector apparatus and needles as described above.

The vent 189V may comprise a resistance to flow of the injectedformulation, and the porous structure 150 may comprise a resistance toflow. The resistance to flow of the vent 189V can be lower than theresistance to flow of the porous structure 150 so as to inhibit releaseof a bolus when the therapeutic formulation is placed in the reservoirchamber. Alternatively, the injector can inject a bolus as describedherein.

FIG. 7A-3 shows a deformable visual indicator 189DS. The deformablevisual indicator can be coupled to a support, for example stop 189S,such that the visual indicator can deform to indicate when the needle ispositioned to an appropriate depth 189SD. The visual indicator can beused with an injector such as a syringe and can be used for injectionsinto one or more of many tissues such as dental, internal tissues duringsurgery and ocular tissues such as the conjunctiva of the eye. Theneedle 189 may comprise a silicon needle, for example a 25 GA or moreneedle, for example a 30 GA needle.

The visual indicator 189DS may comprise a bright color and may comprisea soft deformable material such as silicone, and may have a Shore Ahardness from about 5 to about 30, for example. The stop 189S maycomprise a dark color, such that the deformable indicator becomesvisible when coupled to tissue. Prior to contact with the tissue, thedeformable indicator 189DS has a first width 189DSW1.

FIG. 7A-4 shows the visual indicator 189DS coupled to soft tissue, suchas tissue of an eye, for example the conjunctiva positioned over thepenetrable barrier of the therapeutic device 100. The visual indicatorhas been deformed and comprises a second width 189DSW2 that is greaterthan the first width such that the deformable indicator is visible whenviewed when coupled to the tissue surface. Such visual indication ofcoupling can be helpful to ensure that the correct amount of pressure isapplied by the health care provider and also so that the needle tips islocated at an intended distance below the surface of the tissue.

FIG. 7A-5 shows a therapeutic device 100 coupled to injector 701 withone or more of potentially insufficient force prior to injection orpotentially insufficient depth. As noted above, the therapeutic devicemay provide at least some resistance to flow, and the visual indicator189DS can indicate when operator has applied sufficient force to counterreactive force of the injection. Also, the percent mixing can be relatedto the accuracy of the injection, for example with a bolus injectionthrough the therapeutic device, and placement of the needle tip at depth189SD with an accuracy of better than about 1 mm or less can ensure thatthe mixing and/or exchange amount injections is consistent such that thedosage of therapeutic agent can be delivered accurately.

FIG. 7A-6 shows a therapeutic device 100 coupled to injector 701 withone or more of potentially insufficient force prior to injection orpotentially insufficient depth.

FIG. 7A-7A to FIG. 7A-9B show sliding coupling of a valve to a plungercoupled to a piston to exchange a first intended volume of liquid withinthe reservoir with a volume of formulation of therapeutic agent andclose the valve so as to inject a second volume of liquid through theporous frit structure. FIG. 7A-7A, FIG. 7A-8A, and FIG. 7A-9A show afirst configuration with the injector 701 coupled to a double lumenneedle 189L such that a second lumen 189B injects therapeutic agent 110from a chamber 702C into device 100. A second container 703C is coupledto a first lumen 189A that extends to the chamber of the reservoircontainer and receives liquid from device 100, such that liquid ofdevice 100 is exchanged. A switching valve 703V comprises a first movingcomponent, for example a sliding component, and a second componentcomprising an opening that can be blocked, for example covered, with themoving component. A piston 701P is moved toward the device 100 with aplunger, and the sliding component of switching valve 703V is coupled tothe plunger and piston. When the piston has advanced to exchange anintended amount of liquid and an intended amount of the formulation thetherapeutic agent 110 remains in chamber 702C, the sliding component ofvalve 703 covers and blocks the opening component of valve 703V. Withvalve 703 closed, an intended amount of therapeutic agent is injectedinto device 100, for example such that a bolus amount of therapeuticagent can be injected from device 100. A portion of the formulation oftherapeutic agent injected into device 100 can be retained in device 100for release for an extended time.

The moving component of the valve may comprise one or more of manycomponents such as a ball valve, a sleeve, a gasket, a piston havingholes, or a one way pressure valve, a solenoid, or a servo, for example.

FIG. 7A-10A and FIG. 7A-10B show a first configuration of an injector tomaintain the rate of flow into device to within about +/−50%, forexample to within about +/−25%, such that the time to inject thetherapeutic agent into device 100 remains substantially constant amountdevices and injections. For example, as the release rate index can beless than about 0.5, for example less than about 0.1, for example lessthan about 0.05, and the amount of time to inject fully substantiallyfixed volume of the therapeutic device can be inversely related to therelease rate index.

The injector 701 comprises a mechanism to maintain the rate of flow intothe device and limit a maximum amount of flow, for example with aspring. The mechanism may comprise one or more of a mechanicalmechanism, an electrical mechanism, a pneumatic mechanism, or anhydraulic mechanism, or combinations thereof. Although a mechanicalmechanism is shown, the above described mechanisms can provide similarresults.

The visible indicator 189DS can be used to indicate to the operator thatinjector is coupled to the therapeutic device implanted in the eye at adepth for injection. The operator can then depress the plunger.

The plunger comprises a telescopic joint and a spring, such that thejoint can be slid together such that the plunger is urged downward tocontact the stop. When the plunger is urged downward, the spring iscompressed when the ends of the telescopic joint come together. Thecompressed spring urges the piston toward the therapeutic device suchthat the formulation of therapeutic agent is injected into thetherapeutic device with the force of the spring. The valve 703V canclose as described above. The second portion of the injectioncorresponding to the bolus injection is injected into the therapeuticdevice 100 and through porous structure 150.

FIG. 7B-1 shows a side cross-sectional view of therapeutic device 100comprising a retention structure having a cross-section sized to fit inan elongate incision. The cross-section sized to fit in the elongateincision may comprise a narrow portion 120N of retention structure 120that is sized smaller than the flange 122. The narrow portion 120N sizedto fit in the elongate incision may comprise an elongate cross section120NE sized to fit in the incision. The narrow portion 120N may comprisea cross-section having a first cross-sectional distance across, or firstdimensional width, and a second cross-sectional distance across, orsecond dimensional width, in which the first cross-sectional distanceacross is greater than the second cross-sectional distance across suchthat the narrow portion 120N comprises an elongate cross-sectionalprofile.

The elongate cross section 120NE of the narrow portion 120N can be sizedin many ways to fit the incision. The elongate cross section 120NEcomprises a first dimension longer than a second dimension and maycomprise one or more of many shapes such as dilated slot, dilated slit,lentoid, oval, ovoid, or elliptical. The dilated slit shape and dilatedslot shape may correspond to the shape sclera tissue assumes when cutand dilated. The lentoid shape may correspond to a biconvex lens shape.The elongate cross-section of the narrow portion may comprise a firstcurve along an first axis and a second curve along a second axisdifferent than the first curve.

Similar to the narrow portion 120N of the retention structure, thecontainer reservoir may comprise a cross-sectional profile

FIG. 7B-2 shows an isometric view of the therapeutic device as in FIG.7B-1.

FIG. 7B-3 shows a top view of the therapeutic device as in FIG. 7B-1.

FIG. 7B-4 shows a side cross sectional view along the short side of theretention structure of the therapeutic device as in FIG. 7B-1.

FIG. 7B-5 shows a bottom view of the therapeutic device as in FIG. 7B-1implanted in the sclera.

FIG. 7B-5A shows a cutting tool 710 comprising a blade 714 having awidth 712 corresponding to perimeter 160P of the barrier 160 and theperimeter 160NP of the narrow portion. The cutting tool can be sized tothe narrow portion 120N so as to seal the incision with the narrowportion when the narrow portion is positioned against the sclera. Forexample, the width 712 may comprise about one half of the perimeter 160Pof the barrier 160 and about one half of the perimeter 160NP of thenarrow portion 160N. For example, the outside diameter of the tube ofbarrier 160 may comprise about 3 mm such that the perimeter of 160Pcomprises about 6 mm, and the narrow portion perimeter 160NP maycomprise about 6 mm. The width 712 of the blade 710 may comprise about 3mm such that the incision comprises an opening having a perimeter ofabout 6 mm so as to seal the incision with the narrow portion 160P.Alternatively, perimeter 160P of barrier 160 may comprise a sizeslightly larger than the incision and the perimeter of the narrowportion.

The retention structure comprises a narrow section 120N having a shortdistance 120NS and a long distance 120NL so as to fit in an elongateincision along the pars plana of the eye. The retention structurecomprises an extension 122. The extension of the retention structure120E comprises a short distance across 122S and a long distance across122S, aligned with the short distance 122NS and long distance 122NL ofthe narrow portion 120N of the retention structure 120. The narrowportion 120 may comprise an indentation 1201 sized to receive thesclera.

FIGS. 7B-6A and 7B-6B show distal cross-sectional view and a proximalcross-sectional view, respectively, of therapeutic device 100 comprisinga non-circular cross-sectional size. The porous structure 150 can belocated on a distal end portion of the therapeutic device, and theretention structure 120 can be located on a proximal portion oftherapeutic device 100. The barrier 160 defines a size of reservoir 130.The barrier 160 and reservoir 130 may each comprise an elliptical oroval cross-sectional size, for example. The barrier 160 comprises afirst cross-sectional distance across reservoir 130, and a secondcross-sectional distance across reservoir 130, and the first distanceacross may extend across a long (major) axis of an ellipse and thesecond distance across may extend across a short (minor) axis of theellipse. This elongation of the device along one direction can allow forincreased drug in the reservoir with a decrease interference in vision,for example, as the major axis of the ellipse can be alignedsubstantially with the circumference of the pars plana region of the eyeextending substantially around the cornea of the eye, and the minor axisof the ellipse can be aligned radially with the eye so as to decreaseinterference with vision as the short axis of the ellipse extends towardthe optical axis of the eye corresponding to the patient's line of sightthrough the pupil. Although reference is made to an elliptical or ovalcross-section, many cross-sectional sizes and shapes can be used such asrectangular with a short dimension extending toward the pupil of the eyeand the long dimension extending along the pars plana of the eye.

The retention structure 120 may comprise structures corresponding tostructure of the cross-sectional area. For example, the extension 122may comprise a first distance across and a second distance across, withthe first distance across greater than the second distance across. Theextension may comprise many shapes, such as rectangular, oval, orelliptical, and the long distance across can correspond to the longdistance of the reservoir and barrier. The retention structure 120 maycomprise the narrow portion 120N having an indentation 1201 extendingaround an access port to the therapeutic device, as described above. Theindentation 1201 and extension 122 may each comprise an elliptical oroval profile with a first long (major) axis of the ellipse extending inthe first direction and a second short (minor) axis of the ellipseextending in the second direction. The long axis can be aligned so as toextend circumferentially along the pars plana of the eye, and the shortaxis can be aligned so as to extend toward the pupil of the eye, suchthat the orientation of device 100 can be determined with visualexamination by the treating physician.

FIG. 7B-6C shows an isometric view of the therapeutic device having aretention structure comprising a narrow portion 120N with an elongatecross-sectional size 120NE.

FIG. 7B-6D shows a distal end view of the therapeutic device as in FIG.7B-6C.

FIG. 7B-6E1 shows a side view of the short distance 120NS of the narrowportion 120N of the therapeutic device as in FIG. 7B-6C.

FIG. 7B-6E2 shows a side view of the long distance 120NL of the narrowportion 120N of the therapeutic device 100 as in FIG. 7B-6C.

FIG. 7B-6F shows a proximal view of the therapeutic device as in FIG.7B-6C.

FIG. 7B-6G to FIG. 7B-6I show exploded assembly drawings for thetherapeutic device 100 as in FIGS. 7B-6C to 7B-6F. The assembly drawingsof FIGS. 7B-6G, FIG. 7B-6H and FIG. 7B-61 show isometric and thin sideprofiles views, respectively, of the elongate portion 120NE of thenarrow portion of the retention structure 120N. The therapeutic device100 has an elongate axis 100A.

The penetrable barrier 184, for example the septum, can be inserted intothe access port 180. The penetrable barrier may comprise an elasticmaterial sized such that the penetrable barrier can be inserted into theaccess port 180. The penetrable barrier may comprise one or more elasticmaterials such as siloxane or rubber. The penetrable barrier maycomprise tabs 184T to retain the penetrable barrier in the access port.The penetrable barrier 184 may comprise a beveled upper rim 184R sizedto seal the access port 180. The access port 180 of the reservoircontainer 130 may comprise a beveled upper surface to engage the beveledrim and seal the penetrable barrier against the access port 180 when thetabs 184T engage an inner annular or elongate channel of the accessport. The penetrable barrier 184 may comprise an opaque material, forexample a grey material, for example silicone, such that the penetrablebarrier can be visualized by the patient and treating physician.

The reservoir container 130 of the device may comprise a rigidbiocompatible material that extends at least from the retentionstructure to the rigid porous structure, such that the reservoircomprises a substantially constant volume when the therapeutic agent isreleased with the rigid porous structure so as to maintain a stablerelease rate profile, for example when the patient moves. Alternativelyor in combination, the reservoir container 130 may comprise an opticallytransmissive material such that the reservoir container 130 can betranslucent, for example transparent, such that the chamber of reservoir140 can be visualized when the device is loaded with therapeutic agentoutside the patient prior to implantation, for example when injectedwith a formulation of therapeutic agent prior to implantation in thephysician's office. This visualization of the reservoir 140 can behelpful to ensure that the reservoir 140 is properly filled withtherapeutic agent by the treating physician or assistant prior toimplantation. The reservoir container may comprise one or more of manybiocompatible materials such as acrylates, polymethylmethacrylate,siloxanes, metals, titanium stainless steel, polycarbonate,polyetheretherketone (PEEK), polyethylene, polyethylene terephthalate(PET), polyimide, polyamide-imide, polypropylene, polysulfone,polyurethane, polyvinylidene fluoride or PTFE. The biocompatiblematerial of the reservoir container may comprise an opticallytransmissive material such as one or more of acrylate, polyacrylate,methlymethacraylate, polymethlymethacrylate (PMMA), polyacarbonate orsiloxane. The reservoir container 130 can be machined from a piece ofmaterial, or injection molded, so as to form the retention structure 120comprising flange 122 and the elongate narrow portion 120NE. The flange122 may comprise a translucent material such that the physician canvisualize tissue under the flange to assess the patient and to decreaseappearance of the device 100 when implanted. The reservoir container 130may comprise a channel extending along axis 100A from the access port180 to porous structure 150, such that formulation injected into device100 can be release in accordance with the volume of the reservoir andrelease rate of the porous structure 150 as described herein. The porousstructure 150 can be affixed to the distal end of therapeutic device100, for example with glue. Alternatively or in combination, the distalend of the reservoir container 130 may comprise an inner diameter sizedto receive the porous structure 150, and the reservoir container 130 maycomprise a stop to position the porous structure 150 at a predeterminedlocation on the distal end so as to define a predetermined size ofreservoir 140.

FIG. 7C-1 shows an expandable therapeutic device 790 comprisingexpandable barrier material 160 and support 1605 in an expandedconfiguration for extended release of the therapeutic agent. Theexpanded configuration can store an increased amount of therapeuticagent, for example from about 30 uL to about 100 uL. The expandabledevice comprises a retention structure 120, an expandable reservoir 140.The support 1605 may comprise a resilient material configured forcompression, for example resilient metal or thermoplastic.Alternatively, the expandable support may be bent when expanded. Theexpandable device comprises the porous structure 150 disposed on adistal end, and affixed to the expandable support. The expandable devicemay comprise an access port 180, for example with a penetrable barrier184. In the expanded configuration, the device is substantially clearfrom a majority of the optical path OP of the patient

The support 160S of the barrier 160 can provide a substantially constantvolume of the reservoir in the expanded configuration. The substantiallyconstant volume, for example +/−25%, can be combined with the releaserate index of the porous structure 150 so as to tune the expandedreservoir and porous structure to the volume of therapeutic agent to beinjected into the therapeutic device as described herein. The barrier160 may comprise a thin compliant material, for example a membrane, andthe support 160S can urge the barrier 160 to an expanded configurationso as to define the reservoir chamber having the substantially constantvolume.

FIG. 7C-1A shows the distal end portion of the support 160S. The support160S may comprise struts that extend to an annular flange 160SF thatsupports the porous structure 150 on the distal end of device 100.

FIG. 7C-1B shows the support 160S disposed inside the barrier 160 so asto provide the substantially constant expanded volume of the reservoirchamber.

FIG. 7C-1C shows the support 160S disposed along the inner surface ofthe barrier 160 so as to provide the substantially constant expandedvolume of the reservoir chamber. The support 160 can be bonded to thebarrier 160 in many ways, for example with a bonding agent such as glueor resin, or with thermal bonding. The support 160S can be disposed onthe outside of barrier 160.

Expandable Therapeutic Device Having a Substantially Constant ReservoirChamber Volume Configured to Decrease Cross-Sectional Size for Removal

The therapeutic device 100 may comprise an expandable device that can becollapsible in cross-section for removal and comprises a substantiallyconstant reservoir volume and substantially constant release rate indexwhen expanded such that the device can be tuned to receive an amount offormulation of therapeutic agent. The expandable device may comprise anexpandable therapeutic device comprise the retention structure to coupleto the sclera, a penetrable barrier and a flexible support coupled to aflexible barrier. The flexible support can be expandable from a firstelongate narrow profile configuration having a first length and a firstcross-sectional size to a second wide profile configuration having asecond length and a second cross-sectional size. The second wide profileconfiguration can define a chamber having a substantially constantvolume when placed in the eye, in which the first length greater thanthe second length, and the first cross-sectional size is smaller thanthe second cross-sectional size. The flexible support and the flexiblebarrier have sufficiently flexibility so as to increase the length fromthe second length to the first length and decrease the cross-sectionalsize from the second size to the first size when an elongate structureis advanced through the penetrable barrier.

The therapeutic device may comprise expandable and collapsible containershaped with a support structure, positioned away from visual path so asto increase chamber reservoir volume without inhibiting vision. Thetherapeutic device may comprise a collapsible cross-section for removal.The therapeutic device may comprise a substantially fixed expandedvolume, such that the substantially fixed volume is tuned to receiveinjection of therapeutic agent. The substantially fixed volume maycomprise a volume fixed to within +/−50%, for example to within +/−25%.The therapeutic device may comprise a collapsed cross-sectional size of1 mm or less for insertion and insertion size, but could be up to 2 mm.

The therapeutic device may comprise a volume sized to receives injectionfrom about 1 uL to about 100 uL (most formulations are 50 uL injection),for example a chamber reservoir of 100 uL in the expanded substantiallyfixed volume configuration.

The Expandable support frame may include one or more of the following: asupport frame comprising wire, nitinol, thermoplastic, etc.; coupling toa flexible barrier comprising one or more of a balloon, sheet, membrane,or membrane define the shape of chamber with the support and barrier;support frame can be on inside, outside or within flexible barriermaterial self-expanding material or actuated, or combinations thereof;expandable for small insertion incision, for example when the length ofthe device decreases to expand the cross-sectional size to define thechamber having substantially constant volume, collapsible for removalthrough incision, for example when the length of the device increases todecrease cross-sectional size for removal, one or more supportconfigurations, braided support (elongated/thin to position theexpandable device, e.g. with mandrel). Expansion volume of reservoir maybe limited to no more than 0.2 mL, such that IOP is not substantiallyincreased when the device expands to the substantially constant volumewide profile configuration.

FIG. 7C-1D shows an elongate structure of a removal apparatus insertedinto the expandable and collapsible cross-section device to decrease thecross-sectional width of the device. The removal apparatus may comprisea guide and coupling structure. The coupling structure may comprise oneor more of a u-shaped flange, tines, jaws, clamps, to couple to theretention structure. The guide may comprise one or more of a channel,loop, hole or other structure coupled to the coupling structure to alignthe elongate structure with the therapeutic device to advance theelongate structure through the penetrable barrier and along the axis100A to the distal portion comprising the stop. The stop may comprisethe rigid porous structure 150 or other structure coupled to the support160S.

FIG. 7C-1E shows the first elongate profile configuration of support1605 comprising first length L1 and first width W1.

FIG. 7C-1F shows the second wide profile configuration of support 160Scomprising second length L2 and second width W2.

The support 160S may comprise a first proximal annular portion 160SA,for example a ring structure, a second distal annular portion 160SB, forexample a ring structure, and struts 160SS extending axiallytherebetween. The struts 160SS can extend axially from the firstproximal annular portion 160SA comprising the first ring structure tothe second ring structure. The first proximal portion 160SA may supportthe penetrable barrier 184 and be sized to receive the elongatestructure. The second distal annular portion 160B can be coupled to therigid porous structure 150, for example with the flange, such that theelongate structure can urge the porous structure 150 axially along axis100A so as to increase the length from second length L2 to first lengthL1 to remove the therapeutic device.

The support 160 may comprise a flexible material, for example a shapememory material or flexible metal or plastic, such that the struts 160SSextending from the proximal ring structure to the distal ring structurecan be compressed when placed in the cannula as described above and thenseparate to define the chamber when passed through the cannula in to theeye so as to define the reservoir chamber having the substantiallyconstant volume. When the elongate structure urges the rigid porousstructure away from the proximal end coupled to the coupling so as toincrease the length of device 790, the cross-sectional width isdecreased to remove the expandable therapeutic device 790.

FIG. 7C-2 shows the expandable therapeutic device 790 as in FIG. 7C-1 ina narrow profile configuration suitable for use in an injection lumen.

FIG. 7C-3 shows the expandable therapeutic device as in FIG. 7C-1 in anexpanded profile configuration, suitable for retention, for example withthe sclera.

FIGS. 7C-4A and 7C-4B show an expandable retention structure 792. Theexpandable retention structure 792 can be used with the expandabletherapeutic device 790, or with a substantially fixed reservoir andcontainer device as described above. The expandable retention structure792 comprises many compressible or expandable or resilient materials orcombinations thereof. The expandable retention structure 792 comprise anextension 120E that can expand from the narrow profile configuration tothe expanded configuration, for example with tabs and flanges comprisingresilient material. The upper portion can be inclined proximally and thedistal portion can be inclined distally, such that the retentionstructure expands to engage opposite sides of the sclera. The resilientmaterial may comprise a thermoplastic material, a resilient metal, ashape memory material, and combinations thereof.

FIG. 7D shows therapeutic device 100 comprising porous structure 150positioned in an eye 10 to deliver a therapeutic agent to a targetlocation on or near the retina 26, for example choroidalneovasculaturization of a lesion on or near the retina. For example, thelesion may comprise one or more buckling, folding, bending or separationof the retina from the choroid related to neovascularization ofcorresponding vascular tissue associated with blood supply to theretina, and the neovascular tissue corresponding to the lesion of theretina may be targeted. Work in relation to embodiments indicates thatthe vitreous humor 30 of the eye may comprise convective current flowsthat extend along flow paths 799. The convective flow paths may compriseflow channels. Although small molecules can be delivered to a targetlocation of the retina 26 in accordance with the flow paths, therapeuticagent comprising large molecules, for example with antibody fragments orantibodies, can be delivered substantially with the convective flowpaths as the molecular diffusion of large molecules in the vitreoushumor can be somewhat lower than small molecules.

The therapeutic device can be sized such that porous structure 150 ispositioned along a flow path extending toward a target location of theretina. The therapeutic agent can be released along the flow path, suchthat the flow of vitreous humor transports the therapeutic agent to theretina. The porous structure can be disposed on a distal portion of thetherapeutic device, for example on a distal end, and the reservoir 130can be sized for delivery for the extended time. The retention structure120 can be located on the proximal. The therapeutic device 100 can besized such that the porous structure is positioned in the flow patchcorresponding to the target region. The surgeon may identify a targetregion 798 of the retina, for example corresponding to a lesion, and thetherapeutic device 100 can be positioned along the pars plana or otherlocation such that the therapeutic agent is released to the targetregion.

FIG. 7E shows therapeutic device 100 comprising porous structure 150located on a proximal portion of the device to deliver a therapeuticagent to one or more of the ciliary body or the trabecular meshwork whenimplanted in the eye. The porous structure 150 can be located nearretention structure 120 such that the porous structure is positioned inthe vitreous substantially away from the flow paths extending to retina,as noted above. The porous structure can be located on a side of thetherapeutic device so as to release the therapeutic agent toward atarget tissue. While many therapeutic agents can be used, thetherapeutic agent may comprise a prostaglandin or analog, such asbimatoprost or latanoprost, such that the therapeutic agent can bereleased toward one or more of the ciliary body or trabecular meshworkwhen implanted in the vitreous humor with the retention structurecoupled to the sclera.

FIG. 7F shows therapeutic device 100 comprising porous structure 150oriented to release the therapeutic agent 110 away from the lens andtoward the retina. For example, the therapeutic agent 110 may comprise asteroid, and the steroid can be released from porous structure 150 awayfrom the lens and toward the retina. For example, the porous structurecan be oriented relative to an axis 100A of the therapeutic device. Theouter side of porous structure 150 can be oriented at least partiallytoward the retina and away from the lens, for example along a flow pathas described above so as to treat a target region of the retina. Thebarrier 160 can extend between the porous structure 160 and the lens ofthe eye when implanted such that release of therapeutic agent toward thelens can be inhibited with barrier 160. The retention structure 120 maycomprise a long distance across and a short distance across as describedabove. The porous structure can be oriented in relation to the short andlong distances of the extensions 122, such that the outer side of porousstructure 150 is oriented at least partially toward the retina and alongthe flow path when the long distance of the retention structure extendsalong the pars plana and the short distance extends toward the pupil.

FIG. 7G shows a kit 789 comprising a placement instrument 750, acontainer 780, and a therapeutic device 100 disposed within thecontainer. The reservoir of the therapeutic device 100 disposed in thecontainer may comprise a non-therapeutic solution, for example saline,such that the channels of the porous structure comprise liquid water toinhibit bubble formation when the formulation of therapeutic agent isinjected into the device 100. The kit may also comprise the syringe 188,needle 189 and stop 1895 to insert the needle tip to a maximum stopdistance within the reservoir as described above. The kit may containinstructions for use 789I, and may contain a container 110C comprising aformulation of therapeutic agent.

Tuning of Therapeutic Device for Sustained Release Based on an Injectionof a Formulation

The therapeutic device 100 can be tuned to deliver a target therapeuticconcentration profile based on the volume of formulation injected intothe device. The injected volume may comprise a substantially fixedvolume, for example within about +/−30% of an intended pre-determinedtarget volume. The volume of the reservoir can be sized with the releaserate index so as to release the therapeutic agent for an extended timesubstantially greater than the treatment time of a corresponding bolusinjection. The device can also be tuned to release the therapeutic agentbased on the half life of the therapeutic agent in the eye. The devicevolume and release rate index comprise parameters that can be tunedtogether based on the volume of formulation injected and the half lifeof the therapeutic agent in the eye. The following equations can be usedto determine therapeutic device parameters suitable for tuning thedevice.

Rate=Vr(dCr/dt)=−D(PA/TL)Cr

where Rate=Rate of release of therapeutic agent from deviceCr=concentration of therapeutic agent in reservoirVr=volume of reservoirD=Diffusion constant

PA/TL=RRI

P=porosityA=areaT=tortuosity=F=channel parameter.For a substantially fixed volume injection,

Cr0=(Injection Volume)(Concentration of Formulation)/Vr

Where Cr0=initial concentration in reservoir following injection offormulation

For Injection Volume=50 uL

Cr0=(0.05 mL)(10 mg/mL)/Vr(1000 ug/1 mg)=500 ug/Vr

Rate=x(500 ug)exp(−xt)

where t=time

x=(D/Vr)(PA/TL)

With a mass balance on the vitreous

Vv(dCv/dt)=Rate from device=kVvCv

where Vv=volume of vitreous (about 4.5 ml)Cv=concentration of therapeutic agent in vitreousk=rate of drug from vitreous (proportional to 1/half life of drug invitreous)For the situation appropriate for the embodiments as described hereinwhere Cv remains substantially constant and changes slowly with time(i.e. dCv/dt is approximately 0),

Cv=(Rate from device)/(kVv)

Since kVv is substantially constant, the max value of Cv will correspondto conditions that maximize the Rate from the device. At a given timesince injection into the device (e.g., 180 days), the maximum Cv isfound at the value of x that provides the maximum rate. The optimalvalue of x satisfies

d(Rate)/dx=0 at a given time.

Rate=500(x)exp(−xt)=f(x)g(x) where f(x)=500x and g(x)=exp(−xt)

d(Rate)/dx=f(x)g(x)+f(x)g′(x)=500(1−xt)exp(−xt)

For a given time, t, d(Rate)/dx=0 when 1−xt=0 and xt=1The rate is maximum when (D/Vr)(PA/TL)t=1.For a given volume, optimal PA/TL=optimal RRI=Vr/(Dt)Therefore the highest Cv at a given time, t, occurs for the optimalRRI=(PA/FL) for a given Vr.Also, the ratio (Vr)/(RRI)=(Vr)/(PA/TL)=Dt will determine the optimalrate at the time.

The above equations provide approximate optimized values that, whencombined with numerical simulations, can provide optimal values of Vrand PA/TL. The final optimum value can depend on additional parameters,such as the filling efficiency.

The above parameters can be used to determine the optimal RRI, and thetherapeutic device can be tuned to the volume of formulation injectedinto the device with a device reservoir volume and release rate indexwithin about +/−50% of the optimal values, for example +/−30% of theoptimal values. For example, for an optimal release rate index of theporous structure and an optimal reservoir volume sized to receive apredetermined quantity of therapeutic agent, e.g. 50 uL, so as toachieve therapeutic concentrations above a minimum inhibitoryconcentration for a predetermined extended time such as 90 days, themaximum volume of the reservoir can be limited to no more than abouttwice the optimal volume. This tuning of the reservoir volume and theporous structure to the injected volume of the commercially availableformulation can increase the time of release of therapeutic amounts fromthe device as compared to a much larger reservoir volume that receivesthe same volume of commercially available injectable formulation.Although many examples as described herein show a porous fit structureand reservoir volume tuned together to receive a quantity of formulationand provide release for an extended time, the porous structure tunedwith the reservoir may comprise one or more of a porous frit, apermeable membrane, a semi-permeable membrane, a capillary tube or atortuous channel, nano-structures, nano-channels or sinterednano-particles, and a person of ordinary skill in the art can determinethe release rate characteristics, for example a release rate index, soas to tune the one or more porous structures and the volume to receivethe quantity of the formulation and release therapeutic amounts for anextended time.

As an example, the optimal RRI at 180 days can be determined for areservoir volume of about 125 uL. Based on the above equations(Vr/Dt)=optimal RRI, such that the optimal RRI at 180 days is about0.085 for the 50 uL formulation volume injected into the device. Thecorresponding Cv is about 3.19 ug/mL at 180 days based on the Rate ofdrug released from the device at 180 days and the rate of the drug fromthe vitreous (k corresponding to a half life of about 9 days). A devicewith a container reservoir volume of 63 uL and RRI of 0.044 will alsoprovide the optimal Cv at 180 days since the ratio of Vr to PA/TL isalso optimal. Although an optimal value can be determined, thetherapeutic device can be tuned to provide therapeutic amounts of drugat a targeted time, for example 180 days, with many values of thereservoir volume and many values of the release rate index near theoptimal values, for example within about +/−50% of the optimal values.Although the volume of the reservoir can be substantially fixed, thevolume of the reservoir can vary, for example within about +/−50% aswith an expandable reservoir such as a balloon reservoir.

The half life of the drug in the vitreous humor of the eye can bedetermined based on the therapeutic agent and the type of eye, forexample human, rabbit or monkey, such that the half life may bedetermined based on the species of the eye, for example. With at leastsome animal models the half life of the therapeutic agent in thevitreous humor can be shorter than for human eyes, for example by afactor of about two in at least some instances. For example, thehalf-life of the therapeutic agent Lucentis™ (ranibizumab) can be aboutnine days in the human eye and about two to four days in the rabbit andmonkey animal models. For small molecules, the half life in the vitreoushumor of the human eye can be about two to three hours and can be aboutone hour in the monkey and rabbit animal models. The therapeutic devicecan be tuned to receive the volume of formulation based on the half lifeof the therapeutic agent in the human vitreous humor, or an animalvitreous humor, or combinations thereof. Based on the teachingsdescribed herein, a person of ordinary skill in the art can determineempirically the half life of the therapeutic agent in the eye based onthe type of eye and the therapeutic agent, such that the reservoir andporous structure can be tuned together so as to receive the volume offormulation and provide therapeutic amounts for the extended time.

EXPERIMENTAL Example 1

FIG. 8 shows reservoirs with exit ports of defined diameters fabricatedfrom 1 mL syringes with Luer-Lok™ tips and needles of varying diameter.The needles were trimmed to a total length of 8 mm, where 2 mm extendedbeyond the needle hub. Metal burrs were removed under a microscope. FIG.8-1 shows the needles attached to syringes which were then filled with asolution of 2.4 mg/mL fluorescein sodium, molecular weight 376 Da, inphosphate buffer (Spectrum Chemicals, B-210). Bubbles were removed andthe syringes were adjusted to be able to dispense 0.05 mL. The shape ofthe resulting reservoir is shown in FIG. 8-1. The first expanded regionis defined by the inside of the needle hub and the tip of the syringe.The second expanded region is inside the syringe. The total volume ofthe reservoir is 0.14 mL.

Once filled, the outside of the reservoirs were rinsed of excessfluorescein by submerging in PBS.

FIG. 8-2 shows the reservoirs placed into 4 mL vials containing 1.5 mLbuffer at room temperature. Collars cut from rubber tubing were placedaround the syringe barrels to position the top of the reservoir to matchthe height of buffer in the vial to avoid any pressure differential. Thetops of the vials were sealed with parafilm to avoid evaporation. Atperiodic intervals, the reservoirs were moved to new vials containingbuffer. The amount of fluorescein transported from the reservoir throughthe exit port was determined by measuring the amount of fluorescein inthe vials via absorption of visible light (492 nm).

TABLE 1C Release of Fluorescein through Exit Port Needle ReleaseReservoir Needle ID Area Rate Number Gauge (mm) (mm{circumflex over( )}2) (ug/day) 1 18 0.838 0.552 10.8 2 18 0.838 0.552 9.4 3 23 0.3180.079 1.0 4 23 0.318 0.079 1.2 5 30 0.14 0.015 0.6 6 30 0.14 0.015 0.6

The initial release rate (averaged over 0.5-4 days) is proportional tothe area of the exit port opening.

The cumulative amount released into the vials is shown in FIG. 9. Theamount released in a week ranged from 2 to 20%. An average delivery ratewas determined from the slope for data collected between 0.5 and 4.5days and is reported in Table 1C. FIG. 10 shows that the initial releaserate is approximately proportional to the area of the exit port opening.

Example 2

FIG. 11 shows reservoirs with a porous membrane fabricated by cuttingoff the Luer-Lok tip on 1 mL syringes. The end of the syringe wassmoothed and beveled. A nylon membrane with 0.2 μm pore size was placedover the end of the syringe and secured with a piece of silicone tubing.The inner diameter of the syringe was 4.54 mm, yielding an exposedmembrane area of 16 mm². The piston was removed so that approximately100 mL of 300 mg/mL bovine serum albumin (BSA, Sigma A7906-100G) in PBScould be added. The piston was replaced and moved to remove the air andto push a small amount of the liquid through the membrane. The outsideof the membrane and syringe was rinsed by submerging briefly in water.The reservoirs were then placed into 15 mL vials containing 5 mL PBS.The tops of the vials were sealed with parafilm to avoid evaporation. Atperiodic intervals of 0.5-1 day, the reservoirs were moved to new vialscontaining PBS. Diffusion through the membrane was determined bymeasuring the amount of BSA that accumulated in the vials via absorptionof visible light (280 nm). The delivery rates from two replicates areshown in FIG. 11-1. This data suggests that therapeutic agents ofinterest with molecular weight on the order of 100 kDa will transporteasily through porous membranes with pore sizes of 0.2 um.

Example 3

An experiment was performed to screen chromatographic media (Bio-Rad)for binding to Human IgG (Jackson ImmunoResearch, ChromPure). Columnswere packed with the ten media listed below and were equilibrated in 20mM acetate buffer pH 4.5.

TABLE 2 Macro-Prep t-Butyl HIC Support Macro-Prep DEAE Support CHTCeramic Hydroxyapatite Type I 40 um Macro-Prep CM Support Macro-PrepMethyl HIC Support Macro-Prep Ceramic Hydroxapatite Type II 40 umUNOsphere S Cation Exchange Support UNOsphere Q Strong Anion ExchangeSupport Macro-Prep High S Support Macro-Prep High Q Support

Then, 0.5 mL aliquots of 1 mg/mL antibody in 20 mM acetate buffer pH 4.5were gravity-driven through the column and the collected solution wasassessed qualitatively for color change using a BCA™ protein assay kit(Pierce). Of the media tested, Macro-Prep CM Support, Macro-Prep High SSupport, and Macro-Prep Ceramic Hydroxapatite Type II 40 um eachsuccessfully bound IgG. Subsequently, PBS was washed through the columnsand the IgG was released from all three of these media.

Future Exit Port Studies

The experiments described in Examples 1-3 can be repeated with agitationto explore the impact of mixing induced by eye movement. In addition,the experiments can be performed at body temperature where deliveryrates would be expected to be higher based upon faster diffusion ratesat higher temperature.

Diffusion rates of BSA (MW 69 kDa) should be representative of diffusionrates of Lucentis™ and Avastin™, globular proteins with MW of 49 and 150kDa, respectively. Selected experiments could be repeated to confirmindividual delivery rates of these therapeutic agents.

Device prototypes closer to the embodiments described in the body of thepatent could be fabricated from metals (e.g., titanium or stainlesssteel) or polymers (e.g., silicone or polyurethane). Exit ports ofdefined areas can be created via ablation or photo-etching techniques.In the case of polymers, exit ports can also be created by molding thematerial with a fine wire in place, followed by removal of the wireafter the polymer is cured. Access ports can be created using membranesof silicone or polyurethane. Needle stops and flow diverters can befabricated from metal or a rigid plastic.

Device prototypes can be tested with methods similar to those describedin Example 1. Drug delivery rates can be measured for pristine devicesas well as devices that have been refilled. Methods such as absorbanceand fluorescence can be used to quantitate the amount of therapeuticagent that has been delivered as a function of time. Enzyme-LinkedImmunoSorbent Assays (ELISA) can be used to monitor the stability of thebiological therapeutic agent in the formulations at 37° C. and can beused to determine the concentration of biologically active therapeuticagent delivered as a function of time.

Future Membrane Studies

Experiments could be performed with a range of candidates to identifymembranes that 1) would be a barrier to bacteria and cells without muchresistance during refilling; 2) may contribute to controlling thedelivery rate of the therapeutic agent; and 3) would be biocompatible.Candidate membranes would have pore sizes of 0.2 μm or smaller,approaching the size of the therapeutic agents. A variety of fixturescan be used to secure a membrane between a donor solution and a receiversolution to measure permeation rates. In addition, performance ofmembranes can be tested in device prototypes using methods similar towhat was done in Example 3.

Porous membranes could include cellulose acetate, nylon, polycarbonate,and poly(tetrafluoroethylene) (PTFE), in addition to regeneratedcellulose, polyethersulfone, polyvinylidene fluoride (PVDF).

Developing Binding Formulations and Conditions

Once media and conditions have been screened via the batch orflow-through methods, devices can be fabricated containing the bindingmedia in place or with binding media injected along with the therapeuticagent. Formulations can be prepared with the desired excipients, andtherapeutic agent delivery rates can be monitored similarly to themethod used in Example 1.

Additional media to test for binding include, ion exchange andbioaffinity chromatography media based on a hydrophilic polymericsupport (GE Healthcare) that bind proteins with high capacity, and ahydrophilic packing material from Harvard Apparatus made from poly(vinylalcohol) that binds more protein than silica. Other candidates would beknown to those knowledgeable in the art.

A change in pH could modulate the binding of antibody to media. Forexample, binding of antibody would be expected in a formulation withcationic exchange media at an acidic pH. As the pH becomes more neutral,the antibody may be released from the media. Formulations could betested that provide acidic pH for finite durations (i.e., a few months).Once the pH has become neutral, the release of antibody from the bindingmedia could drive a higher release rate, resulting in a more constantrelease rate profile.

The binding media itself may have some buffering capacity that coulddominate until physiological buffer diffuses into the device.

Alternatively, the formulation could include a buffer with a bufferingcapacity selected to dominate during the first few months. With time,the formulation buffer will diffuse out of the device and physiologicalbuffer will diffuse into the device, which will result in a change of pHtowards physiological pH (i.e., neutral). The kinetics of this changecan be modulated by use of a polymeric buffer, with a higher molecularweight buffer remaining in the device for longer periods of time.Polypeptides are attractive as biocompatible polymeric buffers becausethey degrade to amino acids. Buffers are optimal near their pKa. Thetable below lists the pKa of the side chains of amino acids of interest.

TABLE 3 Amino Acid pKa of side chain L-Aspartic Acid 3.8 L-Glutamic Acid4.3 L-Arginine 12.0 L-Lysine 10.5 L-Histidine 6.08 L-Cysteine 8.28L-Tyrosine 10.1

The formulation could include a polyester, such as PLGA, or otherbiodegradable polymers such as polycaprolactone orpoly-3-hydroxybutyrate, to generate hydrogen ions for a finite amount oftime. The degradation rate could be modulated by, for example, changingthe composition or molecular weight of the PLGA, such that thedegradation is completed within a few months, contributing to reachingneutral pH in the last few months of delivery.

The pH could also be modulated electrochemically. Suitable electrodematerials include inert or non-consumable materials such as platinum orstainless steel. Water hydrolysis occurs at the electrode interfaces andthe products of hydrolysis are hydronium ions at the anode and hydroxylions at the cathode.

Rationale for Device Length

At least some device designs do not extend more than about 6 mm into thevitreous so as to minimize interference with vision. In addition, it canbe beneficial to have the device extend into the vitreous since thendrug can be released a distance from the walls of the globe.Macromolecules, such as antibodies, are primarily eliminated from thevitreous by a convection process rather than a diffusion process. (seeComputer Simulation of Convective and Diffusive Transport ofControlled-Release Drugs in the vitreous Humor, by Stay, M S; Xu, J,Randolph, T W; and V H Barocas, Pharm Res 2003, 20(1), pp. 96-102.)Convection can be driven by the pressure generated by the secretion ofaqueous humor by the ciliary body, with flow in the vitreous directedtowards the retina. With exit ports extending into the vitreous, it maybe more likely that drug will be convected towards the back of the eyeand the central retina, as opposed to a device with ports flush with theglobe likely delivering more of the therapeutic agent to the peripheralretina.

Example 4 Comparison of Predicted Vs. Measured Release Rates for aReservoir with One Orifice

The release study described in Example 1 using 23 and 30 gauge needleswas continued through ten weeks. The results are compared with a modelrelating the change of concentration in the reservoir to the releaserate from the reservoir based upon Fick's Law of diffusion. This simplemodel assumes the concentration in the reservoir is uniform and theconcentration in the receiving fluid or vitreous is negligible. Solvingthe differential equation yields the following cumulative release of atherapeutic agent from a reservoir with one orifice:

Cumulative Release=1−cR/cR0=1−exp((−D A/L V _(R))t),

where:cR=Concentration in reservoirV_(R)=Volume of reservoirD=Diffusion coefficientA=Area of orificeL=Thickness of orificet=Time

FIG. 12 shows the cumulative amount released into the vials over 10weeks and the predicted cumulative amount release. These data show thatthe release from model devices generally agrees with the trend predictedby this model with no adjustable fitting parameters.

Example 5 Release of Protein Through a Cylindrical Sintered PorousTitanium Cylinder

Reservoirs were fabricated from syringes and sintered porous titaniumcylinders (available from Applied Porous Technologies, Inc., MottCorporation or Chand Eisenmann Metallurgical). These were sinteredporous cylinders with a diameter of 0.062 inches and a thickness of0.039 inches prepared from titanium particles. The porosity is 0.17 withmean pore sizes on the order of 3 to 5 micrometers. The porous cylinderis characterized as 0.2 media grade according to measurements of bubblepoint. The porous cylinders were press-fit into sleeves machined fromDelrin. The sleeves exposed one entire planar face to the solution inthe reservoir and the other entire planar face to the receiver solutionin the vials, corresponding to an area of 1.9 square millimeters. Thetips were cut off of 1 mL polypropylene syringes and machined to accepta polymer sleeve with outer diameter slightly larger than the innerdiameter of the syringe. The porous cylinder/sleeve was press-fit intothe modified syringe.

A solution was prepared containing 300 mg/mL bovine serum albumin (BSA,Sigma, A2153-00G) in phosphate buffered saline (PBS, Sigma, P3813).Solution was introduced into the syringes by removing the piston anddispensing approximately 200 microliters into the syringe barrel.Bubbles were tapped to the top and air was expressed out through theporous cylinder. Then BSA solution was expressed through the porouscylinder until the syringe held 100 uL as indicated by the markings onthe syringe. The expressed BSA solution was wiped off and then rinsed bysubmerging in PBS. The reservoirs were then placed into 4 mL vialscontaining 2 mL PBS at room temperature. Collars cut from siliconetubing were placed around the syringe barrels to position the top of thereservoir to match the height of PBS. The silicone tubing fit inside thevials and also served as a stopper to avoid evaporation. At periodicintervals, the reservoirs were moved to new vials containing PBS. Theamount of BSA transported from the reservoir through the porous cylinderwas determined by measuring the amount of BSA in the vials using a BCA™Protein Assay kit (Pierce, 23227).

FIG. 13 shows the measured cumulative release of BSA through a sinteredporous titanium disc and a prediction from the model describing releasethrough a porous body. The Channel Parameter of 1.7 was determined via aleast squares fit between the measured data and the model (MicroSoftExcel). Since the porous cylinder has equal areas exposed to thereservoir and receiving solution, the Channel Parameter suggests atortuosity of 1.7 for porous titanium cylinders prepared from 0.2 mediagrade.

FIG. 13-1 shows the measured cumulative release of BSA of FIG. 13measured to 180 days. The Channel Parameter of 1.6 was determined via aleast squares fit between the measured data and the model (MicroSoftExcel). This corresponds to a Release Rate Index of 0.21 mm. Since theporous cylinder has equal areas exposed to the reservoir and receivingsolution, the Channel Parameter corresponds to an effective path lengthchannel parameter of 1.6 and suggests a tortuosity of 1.6 for poroustitanium cylinders prepared from 0.2 media grade.

Example 6 Release of Protein Through Masked Sintered Porous TitaniumCylinders

Reservoirs were fabricated from syringes and porous sintered titaniumcylinders similar to that described in Example 5. The porous sinteredtitanium cylinders (available from Applied Porous Technologies, Inc.,Mott Corporation or Chand Eisenmann Metallurgical) had a diameter of0.082 inch, a thickness of 0.039 inch, a media grade of 0.2 and wereprepared from titanium particles. The porosity is 0.17 with mean poresizes on the order of 3 to 5 micrometers. The porous cylinder ischaracterized as 0.2 media grade according to measurements of bubblepoint. The porous cylinders were press fit into sleeves machined fromDelrin. The sleeves exposed one entire planar face to the solution inthe reservoir and the other entire planar face to the receiver solutionin the vials, corresponding to an area of 3.4 square millimeters. Thetips were cut off of 1 mL polycarbonate syringes and machined to accepta polymer sleeve with outer diameter slightly larger than the innerdiameter of the syringe. The porous cylinder/sleeve was press fit intothe modified syringe. A kapton film with adhesive was affixed to thesurface exposed to the receiving solution to create a mask and decreasethe exposed area. In the first case, the diameter of the mask was 0.062inches, exposing an area of 1.9 square millimeters to the receivingsolution. In a second case, the diameter of the mask was 0.027 inches,exposing an area of 0.37 square millimeters.

Three conditions were run in this study: 1) 0.062 inch diameter mask,100 uL donor volume, at room temperature in order to compare withreservoirs with unmasked porous cylinders in Example 5; 2) 0.062 inchdiameter mask, 60 uL donor volume, at 37° C.; and 3) 0.027 inch diametermask, 60 uL donor volume, at 37° C. The syringes were filled with asolution containing 300 mg/mL bovine serum albumin (BSA, Sigma,A2153-00G) in phosphate buffered saline (Sigma, P3813), similar toExample 5. In addition, 0.02 wt % of sodium azide (Sigma, 438456-5G) wasadded as a preservative to both the BSA solution placed in thereservoirs and the PBS placed in the receiving vials and both solutionswere filtered through a 0.2 micron filter. This time, the amount of BSAsolution dispensed into the syringe was weighed and the amount expressedthrough the porous cylinder was determined by rinsing and measuring theamount of BSA in the rinse. Assuming unit density for the BSA solution,the amount dispensed was 113+/−2 uL (Condition 1) and 66+/−3 uL(Condition 2). Subtracting off the amount in the rinse yielded a finalreservoir volume of 103+/−5 uL (Condition 1) and 58+/−2 uL (Condition2). The reservoirs were then placed into 5 mL vials containing 1 mL PBSat 37° C. in a heating block. At periodic intervals, the reservoirs weremoved to new vials containing PBS and the BSA concentrations weredetermined in the receiving solutions using the method described inExample 5.

FIG. 14 shows the cumulative release of BSA protein through a maskedsintered porous Titanium disc at Condition 1 (0.062 inch diameter mask,100 uL donor volume, at room temperature) is faster than the releasethrough an unmasked porous cylinder with the same exposed area (datafrom Example 5). Predictions are also shown using the Channel Parameterof 1.7 determined in Example 5, BSA diffusion coefficient at 20° C.(6.1e−7 cm²/s), reservoir volume of 100 uL, and the area of the porouscylinder exposed to the receiver solution (A=1.9 mm²) or the area of theporous cylinder exposed to the reservoir (A=3.4 mm²). The data for themasked porous cylinder matches more closely with larger area exposed tothe reservoir. Hence, this mask with width of 0.7 mm is not sufficientto reduce the effective area of the porous cylinder for the dimensionsof this porous cylinder.

FIG. 15 shows the cumulative release of BSA protein through a maskedsintered porous titanium cylinder at Condition 2 (0.062 inch diametermask, 60 uL donor volume, at 37° C.). The figure also displayspredictions using the Channel Parameter of 1.7 determined in Example 5,BSA diffusion coefficient at 37° C. (9.1e−7 cm²/s), reservoir volume of58 uL, and the area of the porous cylinder exposed to the receiversolution (A=1.9 mm²) or the area of the porous cylinder exposed to thereservoir (A=3.4 mm²). Again, the data for this masked porous cylindermatches more closely with larger area exposed to the reservoir. Theconsistency of the data with the model at two temperatures supports howthe model incorporates the effect of temperature.

FIG. 16 shows the cumulative release of BSA protein through a maskedsintered porous titanium cylinder at Condition 3 (0.027 inch diametermask, 60 uL donor volume, at 37° C.). The figure also displayspredictions using the Channel Parameter of 1.7 determined in Example 5,BSA diffusion coefficient at 37° C. (9.1e−7 cm²/s), reservoir volume of58 uL, and the area of the porous cylinder exposed to the receiversolution (A=0.37 mm²) or the area of the porous cylinder exposed to thereservoir (A=3.4 mm²). This mask achieves a release rate correspondingto an effective area in between the area exposed to the reservoir andthe area exposed to the receiver solution. A combination of the resultsin FIGS. 15 and 16 demonstrate that slower release is achieved using amask that exposes a smaller area to the receiver solution.

FIGS. 13-16 show an unexpected result. Masking of the area of the porousfit structure so as to decrease the exposed area of the porous structuredecreased the release rate less than the corresponding change in area.The release rate through the porous structure corresponds substantiallyto the interconnecting channels of the porous frit structure disposedbetween the first side exposed to the reservoir and the second sideexposed to the receiver solution, such that the rate of release ismaintained when a portion of the porous fit structure is covered. Therate of release of the interconnecting channels correspondssubstantially to an effective area of the porous frit structure, and theeffective area may correspond to an effective area of theinterconnecting channels within the porous structure as shown above. Asthe rate of release is dependent upon the interconnecting channels, therelease rate can be maintained when at least some of the channels areblocked, for example with coverage of a portion of the porous structureor blocking of a portion of the interconnecting channels with particles.

Example 7 Release of Protein Through Sintered Porous Stainless SteelCylinder (Media Grade 0.1)

Prototype devices were fabricated from tubing and sintered porousstainless steel cylinders (available from Applied Porous Technologies,Inc., Mott Corporation or Chand Eisenmann Metallurgical) which arecylindrical with diameter 0.155 inch and thickness 0.188 inch preparedfrom 316L stainless steel particles. The porous cylinder ischaracterized as 0.1 media grade according to measurements of bubblepoint. This study was performed with these large, off-the-shelf porouscylinders with an area of 12 mm² in order to characterize the resistiveproperties of 0.1 media grade stainless steel.

These devices were prepared using Teflon-FEP heat shrink tubing (Zeus,#37950) and a hot air gun to shrink around the porous cylinders on oneend and a custom prepared septum on the other end (Nusil MED1 4013silicone molded to 0.145 inch diameter). The reservoir volume (46+/−2uL) was determined from the difference in weight between empty systemsand systems loaded with PBS. The PBS was loaded by submerging thesystems in PBS and drawing a vacuum. The systems were then sterilized byheating to 250° F., 15 psi for 15 minutes, submerged in PBS inmicrocentrifuge tubes placed in a pressure cooker (Deni, 9760). Two 30Gneedles were inserted into the septum to displace the PBS with BSAsolution. One was used to inject the BSA solution and the other was bentand used as a vent for the displaced PBS. Sufficient BSA solution wasinjected to fill the needle hub of the vent to approximately ¾ full.Similar to Example 6, the BSA and PBS contained sodium azide and thenominal concentration was 300 mg/mL BSA. The devices were placed into1.5 mL microcentrifuge tubes containing 1 mL PBS and kept at 37° C. in aheating block. Pieces of silicone tubing (tight fit with inside of tube,hole for septum) were used to suspend the devices in the PBS with thebottom of the septum approximately the same height as the PBS. Theconcentrations in the first tubes contained BSA from the filling processand were discarded. At periodic intervals, the devices were moved to newtubes containing PBS and the BSA concentrations were determined in thereceiving solutions using the method described in Example 5.

FIG. 17 displays the measured cumulative release of BSA through the 0.1media grade stainless steel sintered titanium discs. Since the Porosity,P, is not available from the vendor at this time, a single parameter ofPorosity divided by Channel Parameter was determined by least squaresfit of the model to the data. Since the sintered porous structure iscylindrical, the Channel Parameter can be interpreted as the Tortuosity,T, and P/T was determined to be equal to 0.07.

Example 8 Release of Protein Through a Sintered Porous Stainless SteelCylinder (Media Grade 0.2)

Prototype devices were fabricated from tubing and sintered porousstainless steel cylinders (available from Applied Porous Technologies,Inc., Mott Corporation or Chand Eisenmann Metallurgical) which arecylindrical with diameter 0.031 inch, and thickness 0.049 inch preparedfrom 316L stainless steel particles. The porous cylinder ischaracterized as 0.2 media grade according to measurements of bubblepoint. This porous cylinder was obtained as a custom order withproperties determined from a previous study with a large diameter 0.2media grade porous stainless steel cylinder (data no shown) andpredictions based on the model described herein. The area of each faceof this porous cylinder is 0.5 mm².

These devices were prepared using Teflon-FEP heat shrink tubing (Zeus,0.125 inch OD) and a hot air gun to shrink around the porous cylinder onone end and a custom prepared septum on the other end (Nusil MED1 4013silicone molded to 0.113 inch diameter). The reservoir volume (17+/−1uL) was determined from the difference in weight between empty systemsand systems filled with PBS. The PBS was loaded by submerging thesystems in PBS and drawing a vacuum. Dry devices were submerged in PBSin microcentrifuge tubes and sterilized by heating to 250° F., 15 psifor 15 minutes in a pressure cooker (Deni, 9760). Two 30G needles wereinserted into the septum to fill the devices with PBS. One was used toinject the PBS and the other was bent and used as a vent. After weighingthe PBS filled devices, two new needles were inserted through the septumand sufficient BSA solution was injected to fill the needle hub of thevent to approximately % full. The remaining details of the experimentare the same as Example 7.

FIG. 18A displays the measured cumulative release of BSA through the 0.2media grade sintered porous stainless steel cylinder. A single parameterof Porosity divided by Channel Parameter was determined to be 0.12 byleast squares fit of the model to the data. Since the sintered porousstructure is cylindrical, the Channel Parameter can be interpreted aseffective length of the interconnecting channels that may correspond theTortuosity, T. Using the Porosity of 0.17 determined by the vendor, theeffective length of the channel that may correspond to the Tortuositywas determined to be 1.4. Furthermore, this corresponds to a PA/FL ratio(Release Rate Index) of 0.0475 mm.

FIG. 18B displays the measured cumulative release of BSA through the 0.2media grade sintered porous stainless steel cylinder for 180 days. Asingle parameter of Porosity divided by Channel Parameter was determinedto be 0.10 by least squares fit of the model to the data. Since thesintered porous structure is cylindrical, the Channel Parameter can beinterpreted an effective length of the inter-connecting channels thatmay correspond to the Tortuosity, T. Using the Porosity of 0.17determined by the vendor, the effective channel length of theinter-connecting channels that may correspond to the Tortuosity wasdetermined to be 1.7. Furthermore, this corresponds to a PA/FL ratio(Release Rate Index) of 0.038 mm.

Example 9 Calculations of Lucentis™ Concentrations in the Vitreous

The vitreous concentrations of a therapeutic agent can be predictedbased on the equations described herein. Table 4 shows the values of theparameters applied for each of Simulation 1, Simulation 2, Simulation 3,Simulation 4, and Simulation 5. The half-life and vitreous volumecorrespond to a monkey model (J. Gaudreault et al., PreclinicalPharmacokinetics of Ranibizumab (rhuFabV2) after a Single IntravitrealAdministration, Invest Ophthalmol Vis Sci 2005; 46: 726-733) (Z. Yao etal., Prevention of Laser Photocoagulation Induced ChoroidalNeovascularization Lesions by Intravitreal Doses of Ranibizumab inCynomolgus Monkeys, ARVO 2009 abstract D906). The parameter PA/FL can bevaried to determine the release rate profile. For example, the value ofA can be about 1 mm², the porosity can be about 0.1 (PA=0.1 mm²) and thelength about 1 mm and the channel fit parameter that may correspond totortuousity can be about 2 (FL-2 mm), such that PA/TL is about 0.05 mm.A person of ordinary skill in the art can determine empirically thearea, porosity, length and channel fit parameter for extended release ofthe therapeutic agent for the extended period based on the teachingsdescribed herein.

TABLE 4A Values Values Values Values Values Parameter Simulation 1Simulation 2 Simulation 3 Simulation 4 Simulation 5 Diffusion coeff(cm2/s) 1.0E−06 1.0E−06 1.0E−06 1.0E−06 1.0E−06 Initial Loading (ug/mL)10000 10000 10000 10000 10000 Reservoir Vol (ml) 0.05 0.01 0.05 0.010.017 PA/FL (mm) 0.0225 0.0225 0.045 0.045 0.047 Half-life (days) 2.632.63 2.63 2.63 2.63 Rate constant, k (1/day) 0.264 0.264 0.264 0.2640.264 Vitreous vol (ml) 1.5 1.5 1.5 1.5 1.5

Table 4B shows the vitreous concentrations calculated for a 0.5 mg bolusinjection of Lucentis™ injected into the eye of a monkey using equationsdescribed herein and the half-life measured for the monkey listed inTable 4A. The first column used the measured Cmax (Gaudreault et al.)while the second used a calculated Cmaxbased on the dose and volume ofthe vitreous. The average concentration of Lucentis™ is about 46 ug/ml.The minimum therapeutic concentration of Lucentis™ is about 0.1 ug/mL,which may correspond to about 100% VGEF inhibition (Gaudreault et al.).Table 4B indicates that a bolus injection of 0.5 mg Lucentis™ maintainsa vitreous concentration above 0.1 ug/mL for about a month whether usingthe measured or calculated Cmax. This is consistent with monthly dosingthat has been shown to be therapeutic in clinical studies.

TABLE 4B Predicted Vitreous Predicted Vitreous Time Conc using Meas CmaxConc using Calc (days) (ug/mL) Cmax (ug/mL) 0 169.00 333.33 1 129.85256.11 2 99.76 196.77 3 76.65 151.18 4 58.89 116.16 5 45.25 89.24 634.76 68.57 7 26.71 52.68 8 20.52 40.48 9 15.77 31.10 10 12.11 23.89 119.31 18.36 12 7.15 14.10 13 5.49 10.84 14 4.22 8.33 15 3.24 6.40 16 2.494.91 17 1.91 3.78 18 1.47 2.90 19 1.13 2.23 20 0.87 1.71 21 0.67 1.32 220.51 1.01 23 0.39 0.78 24 0.30 0.60 25 0.23 0.46 26 0.18 0.35 27 0.140.27 28 0.11 0.21 29 0.08 0.16 30 0.06 0.12 31 0.05 0.09 32 0.04 0.07

Tables 4C1, 4C2, 4C3 4C4, and 4C5 show the calculated concentration ofLucentis™ in the vitreous humor for Simulation 1, Simulation 2,Simulation 3, Simulation 4, and Simulation 5 respectively. These resultsindicate Lucentis™ vitreous concentrations may be maintained above theminimum therapeutic level for about a year or more when released from adevice with porous structure characterized by PA/FL≦0.0225 mm and areservoir volume≧10 uL.

Simulation 5 corresponds to the devices used in the experiment describedin Example 8. This device had a reservoir volume of 17 uL and porousstructure characterized by PA/FL=0.047 mm. When this device is loadedwith Lucentis™, the loading dose corresponds to ⅓ of the 50 uL currentlyinjected monthly. Calculations that predict vitreous concentrationsindicate that this device with one-third of the monthly dose maymaintain Lucentis™ therapeutic concentrations for about 6 months. Whilehalf of the dose is delivered in the first month and more than 98%delivered at 6 months, therapeutic levels may still be maintained for 6months.

The ability of the device to release therapeutic agent for an extendedtime can be described by an effective device half-life. For the devicein Example 8, the effective device half-life is 29 days for delivery ofLucentis™. The device can be configured by selection of the reservoirvolume and a porous structure with an appropriate PA/FL to achieve thedesired effective half-life.

TABLE 4C1 Simulation 1 Predicted Predicted Vitreous Time Rate PredictedConc (days) (ug/day) % CR (ug/mL) 0 1.9 0.0% 4.9 10 1.9 3.8% 4.7 20 1.87.5% 4.5 30 1.7 11.0% 4.4 40 1.7 14.4% 4.2 50 1.6 17.7% 4.0 60 1.5 20.8%3.9 70 1.5 23.8% 3.7 80 1.4 26.7% 3.6 90 1.4 29.5% 3.5 100 1.3 32.2% 3.3110 1.3 34.8% 3.2 120 1.2 37.3% 3.1 130 1.2 39.7% 3.0 140 1.1 42.0% 2.9150 1.1 44.2% 2.7 160 1.0 46.3% 2.6 170 1.0 48.4% 2.5 180 1.0 50.3% 2.4190 0.9 52.2% 2.3 200 0.9 54.0% 2.3 210 0.9 55.8% 2.2 220 0.8 57.5% 2.1230 0.8 59.1% 2.0 240 0.8 60.7% 1.9 250 0.7 62.2% 1.9 260 0.7 63.6% 1.8270 0.7 65.0% 1.7 280 0.7 66.3% 1.7 290 0.6 67.6% 1.6 300 0.6 68.9% 1.5310 0.6 70.0% 1.5 320 0.6 71.2% 1.4 330 0.5 72.3% 1.4 340 0.5 73.3% 1.3350 0.5 74.4% 1.3 360 0.5 75.3% 1.2

TABLE 4C2 Simulation 2 Predicted Predicted Vitreous Time Rate PredictedConc (days) (ug/day) % CR (ug/mL) 0 1.9 0.0% 4.92 10 1.6 17.7% 4.05 201.3 32.2% 3.33 30 1.1 44.2% 2.74 40 0.9 54.0% 2.26 50 0.7 62.2% 1.86 600.6 68.9% 1.53 70 0.5 74.4% 1.26 80 0.4 78.9% 1.04 90 0.3 82.6% 0.85 1000.3 85.7% 0.70 110 0.2 88.2% 0.58 120 0.2 90.3% 0.48 130 0.2 92.0% 0.39140 0.1 93.4% 0.32 150 0.1 94.6% 0.27 160 0.1 95.5% 0.22 170 0.1 96.3%0.18 180 0.1 97.0% 0.15 190 0.0 97.5% 0.12 200 0.0 98.0% 0.10 210 0.098.3% 0.08 220 0.0 98.6% 0.07 230 0.0 98.9% 0.06 240 0.0 99.1% 0.05 2500.0 99.2% 0.04 260 0.0 99.4% 0.03 270 0.0 99.5% 0.03 280 0.0 99.6% 0.02290 0.0 99.6% 0.02 300 0.0 99.7% 0.01 310 0.0 99.8% 0.01 320 0.0 99.8%0.01 330 0.0 99.8% 0.01 340 0.0 99.9% 0.01 350 0.0 99.9% 0.01 360 0.099.9% 0.00

TABLE 4C3 Simulation 3 Predicted Predicted Vitreous Time Rate PredictedConc (days) (ug/day) % CR (ug/mL) 0 3.9 0.0% 9.8 10 3.6 7.5% 9.1 20 3.314.4% 8.4 30 3.1 20.8% 7.8 40 2.8 26.7% 7.2 50 2.6 32.2% 6.7 60 2.437.3% 6.2 70 2.3 42.0% 5.7 80 2.1 46.3% 5.3 90 1.9 50.3% 4.9 100 1.854.0% 4.5 110 1.7 57.5% 4.2 120 1.5 60.7% 3.9 130 1.4 63.6% 3.6 140 1.366.3% 3.3 150 1.2 68.9% 3.1 160 1.1 71.2% 2.8 170 1.0 73.3% 2.6 180 1.075.3% 2.4 190 0.9 77.2% 2.2 200 0.8 78.9% 2.1 210 0.8 80.5% 1.9 220 0.781.9% 1.8 230 0.7 83.3% 1.6 240 0.6 84.5% 1.5 250 0.6 85.7% 1.4 260 0.586.8% 1.3 270 0.5 87.7% 1.2 280 0.4 88.7% 1.1 290 0.4 89.5% 1.0 300 0.490.3% 1.0 310 0.3 91.0% 0.9 320 0.3 91.7% 0.8 330 0.3 92.3% 0.8 340 0.392.9% 0.7 350 0.3 93.4% 0.6 360 0.2 93.9% 0.6

TABLE 4C4 Simulation 4 Predicted Predicted Vitreous Time Rate PredictedConc (days) (ug/day) % CR (ug/mL) 0 3.89 0.0% 9.83 10 2.64 32.2% 6.67 201.79 54.0% 4.52 30 1.21 68.9% 3.06 40 0.82 78.9% 2.08 50 0.56 85.7% 1.4160 0.38 90.3% 0.95 70 0.26 93.4% 0.65 80 0.17 95.5% 0.44 90 0.12 97.0%0.30 100 0.08 98.0% 0.20 110 0.05 98.6% 0.14 120 0.04 99.1% 0.09 1300.02 99.4% 0.06 140 0.02 99.6% 0.04 150 0.01 99.7% 0.03 160 0.01 99.8%0.02 170 0.01 99.9% 0.01 180 0.00 99.9% 0.01 190 0.00 99.9% 0.01 2000.00 100.0% 0.00 210 0.00 100.0% 0.00 220 0.00 100.0% 0.00 230 0.00100.0% 0.00 240 0.00 100.0% 0.00 250 0.00 100.0% 0.00 260 0.00 100.0%0.00 270 0.00 100.0% 0.00 280 0.00 100.0% 0.00 290 0.00 100.0% 0.00 3000.00 100.0% 0.00 310 0.00 100.0% 0.00 320 0.00 100.0% 0.00 330 0.00100.0% 0.00 340 0.00 100.0% 0.00 350 0.00 100.0% 0.00 360 0.00 100.0%0.00

TABLE 4C5 Simulation 5 Predicted Predicted Vitreous Time Rate PredictedConc (days) (ug/day) % CR (ug/mL) 0 4.1 0.0% 10.27 10 3.2 21.2% 8.09 202.5 38.0% 6.37 30 2.0 51.2% 5.02 40 1.6 61.5% 3.95 50 1.2 69.7% 3.11 601.0 76.1% 2.45 70 0.8 81.2% 1.93 80 0.6 85.2% 1.52 90 0.5 88.3% 1.20 1000.4 90.8% 0.94 110 0.3 92.8% 0.74 120 0.2 94.3% 0.58 130 0.2 95.5% 0.46140 0.1 96.5% 0.36 150 0.1 97.2% 0.29 160 0.1 97.8% 0.22 170 0.1 98.3%0.18 180 0.1 98.6% 0.14 190 0.0 98.9% 0.11 200 0.0 99.2% 0.09 210 0.099.3% 0.07 220 0.0 99.5% 0.05 230 0.0 99.6% 0.04 240 0.0 99.7% 0.03 2500.0 99.7% 0.03 260 0.0 99.8% 0.02 270 0.0 99.8% 0.02 280 0.0 99.9% 0.01290 0.0 99.9% 0.01 300 0.0 99.9% 0.01 310 0.0 99.9% 0.01 320 0.0 100.0%0.00 330 0.0 100.0% 0.00 340 0.0 100.0% 0.00 350 0.0 100.0% 0.00 360 0.0100.0% 0.00

Z. Yao et al. (Prevention of Laser Photocoagulation Induced ChoroidalNeovascularization Lesions by Intravitreal Doses of Ranibizumab inCynomolgus Monkeys, ARVO 2009 abstract D906) have performed apreclinical study to determine the lowest efficacious Lucentis™ dose incynomolgus monkeys that leads to 100% prevention of laserphotocoagulation treatment-induced Grade IV choroidal neovascularization(CNV) lesions. ™ This model has been shown to be relevant to AMD.Intravitreal injection of Lucentis™ at all doses tested completelyinhibited the development of Grade IV CNV lesions. Table 4D showspredictions of Lucentis™ vitreous concentrations for the lowest totalamount of Lucentis™ investigated (intravitreal injection of 5 ug on days1, 6, 11, 16, 21 and 26), using the equations described herein andpharmacokinetic parameters listed in Table 4A. This data indicates thatit is not necessary to achieve the high Cmax of a 0.5 mg single bolusinjection in order to be therapeutic.

FIG. 19A compares this predicted profile with that predicted for thedevice in Example 8. This data further supports that the release profilefrom a device in accordance with embodiments of the present inventionmay be therapeutic for at least about 6 months. The single injection of500 ug corresponds to a 50 uL bolus injection of Lucentis™ that cangiven at monthly intervals, and the range of therapeutic concentrationsof Lucentis™ (ranibizumab) in the vitreous extends from about 100 ug/mLto the minimum inhibitory (therapeutic) concentration of about 0.1 ug/mLat about 1 month, for example. The minimum inhibitory concentrationcorresponding to the lower end of the range of therapeuticconcentrations in the vitreous humor can be determined empirically byone of ordinary skill in the art in accordance with the examplesdescribed herein. For example, a lose does study of a series of sixLucentis™ injections, 5 ug each, can be administered so as to provide aconcentration in the vitreous of at least about 1 ug/mL, and thetherapeutic benefit of the injections assessed as described herein.

TABLE 4D Predicted Lucentis Time Vitreous Conc (days) (ug/mL) 0 0.00 13.33 2 2.56 3 1.97 4 1.51 5 1.16 6 4.23 7 3.25 8 2.49 9 1.92 10 1.47 114.46 12 3.43 13 2.64 14 2.02 15 1.56 16 4.53 17 3.48 18 2.67 19 2.05 201.58 21 4.55 22 3.49 23 2.68 24 2.06 25 1.58 26 4.55 27 3.50 28 2.69 292.06 30 1.59 35 0.42 40 0.11 45 0.03 50 0.01 60 0.00 70 0.00 80 0.00 900.00

The concentration profiles of a therapeutic agent comprising Lucentis™were determined as shown below based on the teachings described hereinand with drug half-life of nine days for Lucentis™ in the human eye. Theexamples shown below for injections of the commercially availableformulation Lucentis™ and the nine day half life show unexpectedresults, and that a volume of formulation corresponding to a monthlybolus injection into the device as described herein can providetherapeutic benefit for at least about two months. The device volume andthe porous structure can be tuned to receive the predetermined volume offormulation and provide sustained release for an extended time.Additional tuning of the device can include the half-life of thetherapeutic agent in the eye, for example nine days for Lucentis™, andthe minimum inhibitory concentration of the therapeutic agent asdetermined based on the teachings as described herein.

FIG. 19B shows determined concentrations of Lucentis™ in the vitreoushumor for a first 50 uL injection into a 25 uL device and a second 50 uLinjection at 90 days. The calculations show that the 50 uL dosage of themonthly FDA approved bolus injection can be used to treat the eye forabout 90 days, and that the injections can be repeated to treat the eye,for example at approximately 90 day intervals. The Lucentis™ maycomprise a predetermined amount of the commercially availableformulation injected into the device. The commercially availableformulation of Lucentis™ has a concentration of ranibizumab of 10 mg/mL,although other concentrations can be used for example as describedherein below with reference to a 40 mg/mL solution of injectedranibizumab. The predetermine amount corresponds to the amount of themonthly bolus injection, for example 50 uL. The therapeutic device maycomprise a substantially fixed volume container reservoir having avolume of 25 uL, such that a first 25 uL portion of the 50 uL injectionis contained in the reservoir for sustained and/or controlled releaseand a second 25 uL portion of the 50 uL injection is passed through theporous structure and released into the vitreous with a 25 uL bolus. Thefilling efficiency of the injection into the device may comprise lessthan 100%, and the reservoir volume and injection volume can be adjustedbased on the filling efficiency in accordance with the teachingsdescribed herein. For example, the filling efficiency may compriseapproximately 90%, such that the first portion comprises approximately22.5 uL contained in the chamber of the container reservoir and thesecond portion comprises approximately 27.5 uL passed through the devicefor the 50 uL injected into the therapeutic device. The initialconcentration of Lucentis™ in the vitreous humor corresponds to about 60ug/mL immediately following injection into the reservoir device. Theconcentration of Lucentis™ in the vitreous humor decreases to about 3.2ug/mL at 90 days. A second 50 uL injection of Lucentis™ approximately 90days after the first injection increases the concentration to about 63ug/mL. The concentration of Lucentis™ in the vitreous humor decreases toabout 3.2 ug/mL at 180 days after the first injection and 90 days afterthe second injection. These calculations show that the concentration ofLucentis™ can be continuously maintained above a minimum inhibitoryconcentration of about 3 ug per ml with the 50 uL injection into thedevice. Additional injections can be made, for example every 90 days forseveral years to deliver the therapeutic agent to treat the patient.

FIG. 19C shows determined concentrations of Lucentis™ in the vitreoushumor for a first 50 uL injection into a 32 uL device and a second 50 uLinjection at a time greater than 90 days. The calculations show that the50 uL dosage of the monthly FDA approved bolus injection can be used totreat the eye for about 90 days, and that the injections can be repeatedto treat the eye, for example at approximately 90 day intervals. TheLucentis™ may comprise a predetermined amount of the commerciallyavailable formulation injected into the device. The predetermine amountcorresponds to the amount of the monthly bolus injection, for example 50uL. The therapeutic device may comprise a substantially fixed volumecontainer reservoir having a volume of 32 uL, such that a first 32 uLportion of the 50 uL injection is contained in the reservoir forsustained and/or controlled release and a second 18 uL portion of the 50uL injection is passed through the porous structure and released intothe vitreous with an 18 uL bolus. The filling efficiency of theinjection into the device may comprise less than 100%, and the reservoirvolume and injection volume can be adjusted based on the fillingefficiency in accordance with the teachings described herein. Forexample, the filling efficiency may comprise approximately 90%, suchthat the first portion comprises approximately 29 uL contained in thechamber of the reservoir container and the second portion comprisesapproximately 21 uL passed through the device for the 50 uL of Lucentis™injected into the therapeutic device. The initial concentration ofLucentis™ in the vitreous humor corresponds to about 45 ug/mLimmediately following injection into the reservoir device. Theconcentration of Lucentis™ in the vitreous humor decreases to about 4ug/mL at 90 days. A second 50 uL injection of Lucentis™ approximately 90days after the first injection increases the concentration to about 50ug/mL. The concentration of Lucentis™ in the vitreous humor decreases toabout 4 ug/mL at 180 days after the first injection and 90 days afterthe second injection. These calculations show that the concentration ofLucentis™ can be continuously maintained above a minimum inhibitoryconcentration of about 4 ug per ml with the 50 uL injection into thedevice. Additional injections can be made every 120 days for severalyears to deliver the therapeutic agent to treat the patient. Theinjections can be made more frequently or less frequently, dependingupon the minimum inhibitory concentration, the release rate profile, andthe discretion of the treating physician.

FIG. 19D shows determined concentrations of Lucentis™ in the vitreoushumor for a first 50 uL injection into a 50 uL device and a second 50 uLinjection at 90 days. The calculations show that the 50 uL dosage of themonthly FDA approved bolus injection can be used to treat the eye forabout 90 days, and that the injections can be repeated to treat the eye,for example at approximately 90 day intervals. The Lucentis™ maycomprise a predetermined amount of the commercially availableformulation injected into the device. The filling efficiency of theinjection into the device may comprise less than 100%, and the reservoirvolume and injection volume can be adjusted based on the fillingefficiency in accordance with the teachings described herein. Forexample, the filling efficiency may comprise approximately 90%, suchthat the first portion comprises approximately 45 uL contained in thechamber of the reservoir container and the second portion comprisesapproximately 5 uL passed through the device for the 50 uL of Lucentis™injected into the therapeutic device. The initial concentration ofLucentis™ in the vitreous humor corresponds to about 11 ug/mLimmediately following injection into the reservoir device. Theconcentration of Lucentis™ in the vitreous humor decreases to about 5.8ug/mL at 90 days. A second 50 uL injection of Lucentis™ approximately 90days after the first injection increases the concentration to about 17ug/mL. The concentration of Lucentis™ in the vitreous humor decreases toabout 5.8 ug/mL at 180 days after the first injection and 90 days afterthe second injection. These calculations show that the concentration ofLucentis™ can be continuously maintained above a minimum inhibitoryconcentration of about 5 ug per ml with the 50 uL injection into thedevice. Additional injections can be made, for example every 90 days forseveral years to deliver the therapeutic agent to treat the patient.

FIG. 19E shows determined concentrations of Lucentis™ in the vitreoushumor for a first 50 uL injection into a 50 uL device and a second 50 uLinjection at 90 days. The calculations show that the 50 uL dosage of themonthly FDA approved bolus injection can be used to treat the eye forabout 130 days, and that the injections can be repeated to treat theeye, for example at approximately 120 day intervals. The Lucentis™ maycomprise a predetermined amount of the commercially availableformulation injected into the device. The filling efficiency of theinjection into the device may comprise less than 100%, and the reservoirvolume and injection volume can be adjusted based on the fillingefficiency in accordance with the teachings described herein. Forexample, the filling efficiency may comprise approximately 90%, suchthat the first portion comprises approximately 45 uL contained in thechamber of the reservoir container and the second portion comprisesapproximately 5 uL passed through the device for the 50 uL of Lucentis™injected into the therapeutic device. The initial concentration ofLucentis™ in the vitreous humor corresponds to about 11 ug/mLimmediately following injection into the reservoir device. Theconcentration of Lucentis™ in the vitreous humor decreases to about 4ug/mL at 133 days. A second 50 uL injection of Lucentis™ approximately130 days after the first injection increases the concentration to about15 ug/mL. Based on these calculations, the concentration of Lucentis™ inthe vitreous humor decreases to about 4 ug/mL at 266 days after thefirst injection and 90 days after the second injection. Thesecalculations show that the concentration of Lucentis™ can becontinuously maintained above a minimum inhibitory concentration ofabout 4 ug per ml with the 50 uL injection into the device. Additionalinjections can be made, for example every 90 days for several years todeliver the therapeutic agent to treat the patient.

Although FIGS. 19B to 19P make reference to injections of commerciallyavailable off the shelf formulations of Lucentis™, therapeutic device100 can be similarly configured to release many formulations of thetherapeutic agents as described herein, for example with reference toTable 1A and the Orange Book of FDA approved formulations and similarbooks of approved drugs in many countries, unions and jurisdictions suchas the European Union. For example, based on the teachings describedherein, one can determine empirically the parameters of therapeuticdevice 100 so as to tune the device to receive a injection of acommercially available formulation corresponding to a monthly bolusinjections and release the injected therapeutic agent with amounts abovethe minimum inhibitory concentration for an extended time of at leastabout two months, for example, at least about three months, for example,or about four months, for example.

FIG. 19F shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 50 uL device having arelease rate index of 0.05. The concentration of ranibizumab in thevitreous humor peaks at around 9 ug/mL and is at or above 4 ug/mL forabout 145 days. The concentration remains above about 1 ug/mL for about300 days. The concentration is about 0.6 ug/mL at 360 days, and can besuitable for treatment with a single injection up to one year, based ona minimum inhibitory concentration of about 0.5. The minimum inhibitoryconcentration can be determined empirically by a person of ordinaryskill in the art based on the teachings described herein.

FIG. 19G shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 75 uL device having arelease rate index of 0.05. The concentration of ranibizumab in thevitreous humor peaks at around 6.5 ug/mL and is at or above 4 ug/mL forabout 140 days. The concentration remains above about 1 ug/mL for about360 days.

FIG. 19H shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 100 uL device having arelease rate index of 0.05. The concentration of ranibizumab in thevitreous humor peaks at around 5 ug/mL and is at or above 4 ug/mL forabout 116 days. The concentration remains above about 1 ug/mL for morethan 360 days and is about 1.5 ug/mL at 360 days.

FIG. 19I shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 125 uL device having arelease rate index of 0.05. The concentration of ranibizumab in thevitreous humor peaks at around 4.3 ug/mL and does not equal or exceed 4ug/mL. The concentration remains above about 1 ug/mL for more than 360days and is about 1.5 ug/mL at 360 days.

FIG. 19J shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 150 uL device having arelease rate index of 0.05. The concentration of ranibizumab in thevitreous humor peaks at around 3.5 ug/mL and does not equal or exceed 4ug/mL. The concentration remains above about 1 ug/mL for more than 360days and is about 1.5 ug/mL at 360 days.

FIG. 19K shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 100 uL device having arelease rate index of 0.1. These determined concentrations are similarto the determined concentrations of FIG. 19F, and show that the releaserate index of the porous structure can be tuned with the device volumeto provide therapeutic concentration profile for an extended time. Forexample, by doubling the volume of the reservoir so as to half theconcentration of therapeutic agent in the vitreous, the release rateindex can be doubled so as to provide a similar therapeuticconcentration profile. The concentration of ranibizumab in the vitreoushumor peaks at around 9 ug/mL and is at or above 4 ug/mL for about 145days. The concentration remains above about 1 ug/mL for about 300 days.The concentration is about 0.6 ug/mL at 360 days.

FIGS. 19L to 19P show examples of release rate profiles with 125 uLreservoir devices having the RRI vary from about 0.065 to about 0.105,such that these devices are tuned to receive the 50 uL injection ofLucentis™ and provide sustained release above a minimum inhibitoryconcentration for at least about 180 days. These calculations used adrug half life in the vitreous of 9 days to determine the profiles and100% efficiency of the injection.

FIG. 19L shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.105. The concentration ofranibizumab in the vitreous at 180 days is about 3.128 ug/mL.

FIG. 19M shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.095. The concentration ofranibizumab in the vitreous at 180 days is about 3.174 ug/mL.

FIG. 19N shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.085. The concentration ofranibizumab in the vitreous at 180 days is about 3.185 ug/mL.

FIG. 19O shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.075. The concentration ofranibizumab in the vitreous at 180 days is about 3.152 ug/mL.

FIG. 19P shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.065. The concentration ofranibizumab in the vitreous at 180 days is about 3.065 ug/mL.

The optimal RRI for the concentration of ranibizumab at 180 days for areservoir volume of 125 uL and a 50 uL injection of Lucentis™ can becalculated based on the equations as described herein, and is about0.085. Although the optimal value is 0.085, the above graphs show thatthe reservoir and release rate index can be tuned to provide therapeuticamounts of ranibizumab above a minimum inhibitory concentration of 3ug/mL with many values of the RRI and reservoir volume, for examplevalues within about +/−30% to +/−50% of the optimal values for thepredetermined quantity of Lucentis™ formulation.

Table 4E shows values of parameters used to determine the ranibizumabconcentration profiles as in FIGS. 19K to 19P.

TABLE 4E Diffusion coeff (cm2/s) 1.0E−06 Initial Loading (ug/mL) 10000Reservoir Vol (ml) 0.125 PA/TL (mm) varied Half-life (days) 9 Rateconstant, k (1/day) 0.077 Vitreous vol (ml) 4.5 Volume injected (mL)0.05 Time step (days) 0.1 Time between refills (days) 180 RefillEfficiency 100%

The therapeutic concentration profiles of examples of FIGS. 19B to 19Pwere determined with a nine day half-life of the drug in the vitreoushumor of the human eye. The therapeutic concentration profiles can bescaled in accordance with the half life of the therapeutic agent in theeye. For example, with an eighteen day half life, the concentration inthese examples will be approximately twice the values shown in the graphat the extended times, and with a 4.5 day half-life, the concentrationswill be approximately half the values shown with the extended times. Asan example, a drug half life of eighteen days instead of nine days willcorrespond to a concentration of about 1.4 ug/mL at 360 days instead ofabout 0.6 ug/mL as shown in FIGS. 19F and 19K. This scaling of theconcentration profile based on drug half life in the vitreous can beused to tune the volume and sustained release structures of thetherapeutic device, for example in combination with the minimuminhibitory concentration. Although the above examples were calculatedfor Lucentis™, similar calculations can be performed for therapeuticagents and formulations as described herein, for example as describedherein with reference to Table 1A.

Based on the teachings described herein, a person of ordinary skill inthe art can determine the release rate index and volume of thetherapeutic agent based on the volume of formulation injected into thedevice and minimum inhibitory concentration. This tuning of the devicevolume and release rate index based on the volume of formulationinjected can produce unexpected results. For example, with a clinicallybeneficial minimum inhibitory concentration of about 4 ug/mL, a singlebolus injection corresponding to a one month injection can provide atherapeutic benefit for an unexpected three or more months, such as fourmonths. Also, for a clinically beneficial minimum inhibitoryconcentration of at least about 1.5 ug/mL, a single bolus injectioncorresponding to a one month injection can provide a therapeutic benefitfor an unexpected twelve or more months. The clinically beneficialminimum inhibitory concentration can be determined empirically based onclinical studies as described herein.

Although the examples of FIGS. 19F to 19K assumed a filling efficiencyof one hundred percent, a person of ordinary skill in the art based onthe teachings as described herein can determine the release rateprofiles for filling efficiencies less than 100%, for example with 90%filling efficiency as shown above. Such filling efficiencies can beachieved with injector apparatus and needles as described herein, forexample with reference to FIGS. 7, 7A, 7A1 and 7A2.

FIG. 19Q shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL concentrated Lucentis™ (40 mg/mL) injection into a 10uL device having a release rate index of 0.01 and in which theranibizumab has a half life in the vitreous humor of about nine days.These data show that an injection of 10 uL of concentrated (40 mg/mL)Lucentis™ into a 10 uL reservoir device can maintain the concentrationof Lucentis™ above at least about 2 ug/mL for at least about 180 dayswhen the half life of Lucentis™ in the vitreous is at least about ninedays, and that the device can provide therapeutic concentrations for anextended time of at least about 180 days when the minimum inhibitoryconcentration comprises no more than about 2 ug/mL.

FIG. 19R shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL concentrated Lucentis™ (40 mg/mL) injection into a 10uL device having a release rate index of 0.01 and in which theranibizumab has a half life in the vitreous humor of about five days.These data show that an injection of 10 uL of concentrated (40 mg/mL)Lucentis™ into a 10 uL reservoir device can maintain the concentrationof Lucentis™ above at least about 1 ug/mL for at least about 180 dayswhen the half life of Lucentis™ in the vitreous is at least about fivedays, and that the device can provide therapeutic concentrations for anextended time of at least about 180 days when the minimum inhibitoryconcentration comprises no more than about 1 ug/mL.

FIG. 19S shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL standard Lucentis™ (10 mg/mL) injection into a 10 uLdevice having a release rate index of 0.01 and in which the ranibizumabhas a half life in the vitreous humor of about nine days. These datashow that an injection of 10 uL of standard commercially available (10mg/mL) Lucentis™ into a 10 uL reservoir device can maintain theconcentration of Lucentis™ above at least about 0.5 ug/mL for at leastabout 180 days when the half life of Lucentis™ in the vitreous is atleast about nine days, and that the device can provide therapeuticconcentrations for an extended time of at least about 180 days when theminimum inhibitory concentration comprises no more than about 0.5 ug/mL.

FIG. 19T shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL standard Lucentis™ (10 mg/mL) injection into a 10 uLdevice having a release rate index of 0.01 and in which the ranibizumabhas a half life in the vitreous humor of about five days. These datashow that an injection of 10 uL of standard commercially available (10mg/mL) Lucentis™ into a 10 uL reservoir device can maintain theconcentration of Lucentis™ above at least about 0.25 ug/mL for at leastabout 180 days when the half life of Lucentis™ in the vitreous is atleast about five days, and that the device can provide therapeuticconcentrations for an extended time of at least about 180 days when theminimum inhibitory concentration comprises no more than about 0.25ug/mL.

Example 10 Calculations of Target Device Characteristics for a DeviceReleasing Drug from a Suspension

Triamcinolone acetonide is a corticosteroid used to treat uveitis andother diseases involving ocular inflammation. A 4 mg intravitrealinjection of a suspension of triamcinolone acetonide may be administeredto patients unresponsive to topical corticosteroids. Calculations asdescribed herein were performed to determine the characteristics of adevice that would release therapeutic amounts for an extended period oftime.

Consider a device with 10 uL reservoir volume loaded with 0.4 mg using acommercial drug product (40 mg/mL triamcinolone acetonide). Calculationswere performed using a value of 19 ug/mL for the solubility oftriamcinolone acetonide measured at 37° C. in 0.2 M potassium chlorideand a diffusion coefficient of 5e−6 cm²/s representative of a smallmolecule. The target release rate is 1 ug/day based upon publishedclinical data. As an example, consider the 0.2 media grade stainlesssteel characterized in Example 8 with P/F=˜0.12 and a thickness of 0.5mm. Using these values, the calculations suggest that therapeuticrelease rates could be achieved with a device containing a porouscylinder with an area of 5 mm². This could be achieved with acylindrical device having an inner diameter of 2 mm and a length ofporous tubing of 1 mm. Alternatively, the end of the device could be aporous cup with height of 0.8 mm (0.5 mm thick porous face plus 0.3 mmlength) of porous tubing.

Assuming a typical value of 3 hours for the half-life of a smallmolecule in the vitreous, these calculations suggest the device willachieve a steady state triamcinolone acetonide vitreous concentration of0.12 ug/mL.

Example 11 Calculation of Release Rate Profile for a Therapeutic AgentSuspension Disposed in the Reservoir and Released Through the PorousFrit Structure

FIG. 20 shows a calculated time release profile of a therapeutic agentsuspension in a reservoir as in Example 10. Triamcinolone Acetonideconcentrations in human vitreous were determined for a 10 uL device withRRI of 1.2 mm and shown. The calculations were based on the equationsshown above for the suspension. The profile was generated with numericalsimulation. Assuming a constant delivery rate of 1 ug/day startinginstantaneously at T=0, the concentration in the vitreous of a human eyecan reach within 99% of the steady state value in 1 day. At the otherend of the drug release profile, the simulation shows the vitreousconcentration when substantially all of the solid drug is gone; morethan 99% of the dissolved drug is delivered within a day.

Assuming a typical value of 3 hours for the half-life of a smallmolecule in the vitreous, these calculations indicate that the devicewill achieve a substantially steady state triamcinolone acetonidevitreous concentration of 0.12 ug/mL in the rabbit or monkey (vitreousvolume of 1.5 mL) or 0.04 ug/mL in the human eye (vitreous volume of 4.5mL). The steady state vitreous concentration are maintained until thereis no longer solid triamcinolone acetonide of the suspension in thereservoir. As shown in FIG. 20, a device with a 10 uL reservoir volumeand Release Rate Index of 1.2 mm can produce substantially constant drugconcentration amounts in the human vitreous for approx. 400 days.Additional experimental and clinical studies based on the teachingsdescribed herein can be conducted to determine the release rate profilein situ in human patients, and the drug reservoir volume and releaserate index configured appropriately for therapeutic benefit for a targettime of drug release. The substantially constant drug concentrationamounts can provide substantial therapy and decrease side effects.Similar studies can be conducted with many suspensions of manytherapeutic agents as described herein, for example suspensions ofcorticosteroids and analogues thereof as described herein.

Example 12 Measured of Release Rate Profiles for Avastin™ Through thePorous Frit Structures Coupled to Reservoirs of Different Sizes andDependence of Release Rate Profile on Reservoir Size

FIG. 21 shows a release rate profiles of therapeutic devices comprisingsubstantially similar porous frit structures and a 16 uL reservoir and a33 uL reservoir. The release rate index of each fit was approximately0.02. The release rate for two therapeutic devices each comprising a 16uL reservoir and two therapeutic devices each comprising a 33 uLreservoir are shown. The device comprising the 33 uL reservoir releasedthe Avastin™ at approximately twice the rate of the device comprising 16uL reservoir. These measured data show that the release rate index andreservoir size can determine the release rate profile, such that therelease rate index and reservoir can be configured to release thetherapeutic agent for an extended time.

First Study: The data were measured with a 16 uL volume reservoir asfollows: 25 mg/mL Avastin™; Frit #2 (0.031×0.049″, media grade 0.2 um,316L SS, Mott Corporation); Substantially similar materials as Example 8above (Teflon heat shrink tubing and silicone septum); 37C; Data istruncated when one of two replicates formed a bubble. See data in Table5A below.

Second Study: The data were measured with a 33 uL reservoir as follows:25 mg/mL Avastin™; Frit #2 (0.031×0.049″, media grade 0.2 um, 316L SS,Mott Corporation); Machined from solid beading, closed with a metal rod;37C; Data is truncated when one of two replicates formed a bubble.

TABLE 5A Measured Release of Avastin ™ and RRI. Volume (uL) Device RRI(mm) SS (ug/day)2 33 1 0.015 0.35 33 2 0.018 0.16 16 1 0.018 0.05 16 20.022 0.06 Mean 0.018 % CV 16%

SS is the average of the squared difference between predicted andmeasured rates, and % CV refers to the coefficient of variation, a knownstatistical parameter.

Example 13 Measured Release Rate Profiles for Avastin™ Through thePorous Frit Structures

FIG. 22A shows cumulative release for Avastin™ with porous fritstructures having a thickness of 0.049″. The experiments used: 25 mg/mLAvastin™; Frit #2 (0.031×0.049″, media grade 0.2 um, 316L SS, MottCorporation); Machined polycarbonate surrogate with screw; ReservoirVolume 37 uL; 37C. The device number and corresponding RRI's for eachtested device are listed in Table 5B below. The determined RRI based onmeasurements is 0.02, consistent with the model for release of thetherapeutic agent as described herein. Although some variability isnoted with regards to the measured RRI for each test device, the RRI foreach device can be used to determine the release of the therapeuticagent, and the porous structure can be further characterized with gasflow as described herein to determine the RRI prior to placement in thepatient.

TABLE 5B Device RRI (mm) SS (ug/day)2  1 0.029 26.0  2 0.027 8.5  50.018 3.7 30 0.013 0.1 31 0.013 0.1 32 0.015 0.7 33 0.022 30.5 Mean0.020 % CV 34%

FIG. 22B1 shows cumulative release for Avastin™ with porous fritstructures having a thickness of 0.029″. The experiments used: 25 mg/mLAvastin™; Frit #3 (0.038×0.029″, media grade 0.2 um, 316L SS, MottCorporation); Machined polycarbonate surrogate with screw; ReservoirVolume 37 uL; 37C. The device number and corresponding RRI's for eachtested device are listed in Table 5C below. The determined RRI based onmeasurements is 0.034, consistent with the model for release of thetherapeutic agent as described herein. Although some variability isnoted with regards to the measured RRI for each test device, the RRI foreach device can be used to determine the release of the therapeuticagent, and the porous structure can be further characterized with gasflow as described herein to determine the RRI prior to placement in thepatient.

TABLE 5C Device RRI (mm) SS (ug/day)2  9 0.033 0.7 10 0.044 10.8 130.030 0.7 27 0.043 15.8 28 0.033 2.6 34 0.030 0.9 35 0.027 0.3 36 0.0345.5 Mean 0.034 % CV 19%

Table 5D shows an update to Table 5B showing experimental results for upto 130 days. Similarly, Table 5E is an update to Table 5C. In bothcases, the RRI was determined by fitting the rate data from each device.For the analysis of data up to 130 days, the first data point isexcluded from the fit because the model assumes the maximum deliveryrate occurs at time zero while there is some startup time oftenassociated with measured release profiles. The startup time may berelated to the time it takes to displace all of the air in the frit. Useof different techniques to displace the air in the frit may reduce thestartup time.

This early data has some noise that appears to be related toexperimental issues such as contamination from excess protein that ispresent on the screw from filling the device and was not completelyrinsed off at the start of the experiment. The contamination appears tooccur randomly as receiver liquid may rinse off the protein whiletransferring the device from vial to vial at some time points but notothers. A more accurate assessment of RRI can be obtained by usingdevices that had fewer or no outliers, as indicated by low values of SS.When this is done, the RRIs from Table 5D and 5E are 0.014 and 0.030 mm,respectively. Similar values for RRI are obtained from data up to 45days and data up to 130 days, supporting the validity of the model.

TABLE 5D Up to 45 Days Up to 130 Days SS SS Device RRI (mm)(ug/day){circumflex over ( )}2 RRI (mm) (ug/day){circumflex over ( )}2 1 0.029 26.0 0.032 13.7  2 0.027 8.5 0.028 5.5  5 0.018 3.7 0.014 1.730 0.013 0.1 0.021 4.8 31 0.013 0.1 0.022 9.3 32 0.015 0.7 0.023 3.4 330.022 30.5 0.028 16.4 Mean 0.020 0.024 % CV 34% 24% Mean for 0.014 0.014SS < 2

TABLE 5E Up to 45 Days Up to 130 Days SS SS Device RRI (mm)(ug/day){circumflex over ( )}2 RRI (mm) (ug/day){circumflex over ( )}2 9 0.033 0.7 0.034 4.4 10 0.044 10.8 0.034 2.0 13 0.030 0.7 0.044 11.627 0.043 15.8 0.045 6.8 28 0.033 2.6 0.031 0.5 34 0.030 0.9 0.030 0.7 350.027 0.3 0.029 1.3 36 0.034 5.5 0.034 5.9 Mean 0.034 0.035 % CV 19% 17%Mean for 0.030 0.030 SS < 2

FIG. 22B2 shows rate of release for Avastin™ with porous frit structureshaving a thickness of 0.029″ as in FIG. 22B1. The rate of release can bedetermined from the measurements and the cumulative release. Theoutliers in this data can be related to measurement error, such ascontamination that provides a signal in the mBCA protein assay.

FIG. 23A shows cumulative release for Avastin™ with a reservoir volumeof 20 uL.

The experiment used: 25 mg/mL Avastin™; Frit #6 (0.038×0.029″, mediagrade 0.2 um, 316L SS, Mott Corporation); Machined polycarbonatesurrogate with screw; 37C. The determined RRI based on measurements is0.05 mm, consistent with the model for release of the therapeutic agentas described herein.

FIG. 23A-1 shows cumulative release to about 90 days for Avastin™ with areservoir volume of 20 uL as in FIG. 23A. The RRI of 0.053 mmcorresponds substantially to the RRI of 0.05 of FIG. 23 and demonstratesstability of the release of therapeutic agent through the porousstructure.

FIG. 23B shows rate of release as in FIG. 23A. The release rate datashow a rate of release from about 5 ug per day to about 8 ug per day.Although the initial release rate at the first day is slightly lowerthan subsequent rates, the rate of release is sufficiently high toprovide therapeutic effect in accordance with the drug release model.Although there can be an initial period of about a few days for therelease rate profile to develop, possibly related to wetting of theinterconnecting channels of the porous structure, the release rateprofile corresponds substantially to the release rate index (RRI) of0.05. Based on the teachings described herein, a person of ordinaryskill in the art could determine the release rate profile withadditional data for an extended time of at least about one month, forexample at least about three months, six months or more, so as todetermine the release rate profile for an extended time.

FIG. 23B-1 shows rate of release as in FIG. 23A-1.

FIG. 24A shows cumulative release for Avastin™ with a 0.1 media gradeporous fit structure. This experiment used: 25 mg/mL Avastin™; Frit #5(0.038×0.029″, media grade 0.1 um, 316L SS, Mott Corporation); Machinedpolycarbonate surrogate with screw; Reservoir Volume 20 uL; 37C. Thedetermined RRI based on measurements is 0.03, consistent with the modelfor release of the therapeutic agent as described herein.

FIG. 24A-1 shows cumulative to about 90 days release for Avastin™ with a0.1 media grade porous fit structure as in FIG. 24A. The release rate of0.038 mm corresponds substantially to the release rate of 0.03 of FIG.24A and demonstrates the stability of release of the therapeutic agentthrough the porous structure.

FIG. 24B shows rate of release as in FIG. 24A. The release rate datashow a rate of release from about 2 ug per day to about 6 ug per day.Although the initial release rate at the first day is slightly lowerthan subsequent rates, the rate of release is sufficiently high toprovide therapeutic effect in accordance with the drug release model.Although there can be an initial period of a few days for the releaserate profile to develop, possibly related to wetting of theinterconnecting channels of the porous structure, the release rateprofile corresponds substantially to the release rate index (RRI) of0.03. Based on the teachings described herein, a person of ordinaryskill in the art could determine the release rate profile withadditional data for an extended time of at least about one month, forexample at least about three months, six months or more, so as todetermine the release rate profile for an extended time.

FIG. 24B-1 shows rate of release as in FIG. 24A-1.

Example 14 Determination of Therapeutic Device Size and Lifetime Basedon Minimum Inhibitory Concentration In Vivo of Therapeutic Agent

Numerical calculations were performed to determine therapeutic devicesizes, release rate profiles and expected therapeutic agentconcentration in the reservoir. The concentration in the reservoir maycorrespond to the useful lifetime of the device, or time betweeninjections of therapeutic agent into the reservoir or other replacementof the therapeutic agent.

Table 6A shows the number days of therapeutic agent is released from thedevice with concentration amounts at or above the MIC. These number ofdays correspond to an effective lifetime of the device or effective timebetween injections into the device. The calculations show the number ofdays of the extended time release based the RRI and MIC for a 20 uLreservoir volume having a drug concentration disposed therein of 10mg/ml. The RRI ranged from 0.01 to 0.1 and the MIC ranged from 0.1 to10, and can be determined with experimental and clinical studies asdescribed herein. The half-life of therapeutic agent in the vitreous wasmodeled as 9 days, based on human data. The Cmax indicates the maximumconcentration of therapeutic agent in the vitreous humor, for examplewithin a few days of placement or injection of the therapeutic agent inthe device These data indicate that the device can maintain theconcentration of therapeutic agent for about 756 days, 385 days, 224days, and 62 day for MIC's of 0.1, 0.5, 1, 2 and 4 ug/ml, respectively.For example, the therapeutic agent may comprise Lucentis™ having an MICof about 0.5 and the device may maintain therapeutic concentrations ofthe agent for one year. These numerical data also show a concentrationof therapeutic agent released from the device within a range of thecurrent clinical bolus injections. For example, the Cmax ranges from 2.1to 11.9 based on the RRI from 0.01 to 0.1 respectively, such that themaximum release of therapeutic agent such as Lucentis™ is within a saferange for the patient.

A person of ordinary skill in the art can conduct experiments todetermine the stability of the therapeutic agent such as Lucentis™ inthe reservoir, and adjust the size of the reservoir, time betweeninjections or removal. The therapeutic agent can be selected andformulated so as to comprise a stability suitable for use in thetherapeutic device.

TABLE 6A Calculations for Time (days) above MIC (20 μL Reservoir Volume,T½ = 9 days, Drug Conc. in Reservoir = 10 mg/ml) Cmax MIC (μg/ml) RRI(μg/ml) 0.1 0.5 1 2 4 7 10 0.01 2.1 756 385 224 62 0 0 0 0.02 3.8 467280 200 119 0 0 0 0.04 6.5 281 188 148 108 66 0 0 0.06 8.6 209 147 12093 65 40 0 0.08 10.4 170 124 103 83 61 42 14 0.1 11.9 146 109 92 75 5842 30

Table 6B. Shows calculations for time (days) above the MIC for atherapeutic device comprising a 20 μL Volume, Vitreous T1/2=9 days, andDrug Conc. in Reservoir=40 mg/ml. The embodiments of Table 6B includesimilar components to the embodiments of Table 6A and the improved timeabove MIC achieved with concentration of 40 mg/ml. For example, the timeabove the MIC can be 1079, 706, 546, 385, 225, 95, for MIC's of 0.1,0.5, 1, 2, 4, and 7 ug/ml, respectively. For example, the therapeuticagent may comprise Lucentis™ having an MIC of about 0.5 and the devicemay maintain therapeutic concentrations of the therapeutic agent forabout 2 years. These numerical data also show a concentration oftherapeutic agent released from the device within a range of the currentclinical bolus injections. For example, the Cmax ranges from 8.4 to 47.6based on the RRI from 0.01 to 0.1 respectively, such that the maximumrelease of therapeutic agent such as Lucentis™ is within a safe rangefor the patient.

A person of ordinary skill in the art can conduct experiments todetermine the stability of the therapeutic agent such as Lucentis™ inthe reservoir, and adjust the size of the reservoir, time betweeninjections or removal. The therapeutic agent can be selected andformulated so as to comprise a stability suitable for use in thetherapeutic device.

TABLE 6B Calculations for Time (days) above MIC (20 μL Volume, T½ = 9days, Drug Conc. in Reservoir = 40 mg/ml) Cmax MIC (μg/ml) RRI (μg/ml)0.1 0.5 1 2 4 7 10 0.01 8.4 1079 706 546 385 225 95 0 0.02 15.1 626 440360 280 200 135 93 0.04 25.9 361 268 228 188 148 115 94 0.06 34.4 262200 174 147 120 98 84 0.08 41.5 210 164 144 124 103 87 76 0.1 47.6 179141 125 109 92 79 70

Table 6C. Shows calculations for time (days) above the MIC for atherapeutic device comprising a 50 μL Volume, Vitreous T1/2=9 days, andDrug Conc. in Reservoir=40 mg/ml. The embodiments of Table 6B includesimilar components to the embodiments of Table 6A and the improved timeabove MIC achieved with concentration of 40 mg/ml. For example, the timeabove the MIC can be 2706, 1737, 1347, 944, 542 and 218, for MIC's of0.1, 0.5, 1, 2, 4, and 7 ug/ml, respectively. For example, thetherapeutic agent may comprise Lucentis™ having an MIC of about 0.5 andthe device may maintain therapeutic concentrations of the therapeuticagent for more than about 2 years. These numerical data also show aconcentration of therapeutic agent released from the device within arange of the current clinical bolus injections. For example, the Cmaxranges from 9.1 to 64.7 ug/ml based on the RRI from 0.01 to 0.1respectively, such that the maximum release of therapeutic agent such asLucentis™ is within a safe range for the patient.

A person of ordinary skill in the art can conduct experiments todetermine the stability of the therapeutic agent such as Lucentis™ inthe reservoir, and adjust the size of the reservoir, time betweeninjections or removal. The therapeutic agent can be selected andformulated so as to comprise a stability suitable for use in thetherapeutic device.

TABLE 6C Calculations for Time (days) above MIC (50 μL Volume, T½ = 9days, Drug Conc. in Reservoir = 40 mg/ml) Cmax MIC (μg/ml) RRI (μg/ml)0.1 0.5 1 2 4 7 10 0.01 9.1 2706 1737 1347 944 542 218 0 0.02 17.2 15601082 880 679 478 316 213 0.04 31.5 887 648 547 446 346 265 213 0.06 43.8635 476 408 341 274 220 186 0.08 54.8 501 381 331 281 230 190 164 0.164.7 417 321 281 240 200 168 147

The examples shown in Tables 6A to 6C can be modified by one of ordinaryskill in the art in many ways based on the teachings described herein.For example, the 50 uL reservoir may comprise an expanded configurationof the reservoir after injection of the therapeutic device. Thereservoir and/or quantity of therapeutic agent can be adjusted so as toprovide release for a desired extended time.

The porous fit structure as described herein can be used with manytherapeutic agents, and may limit release of therapeutic agent that hasdegraded so as to form a particulate, for example. Work in relation toembodiments suggests that at least some therapeutic agents can degradeso as to form a particulate and that the particulate comprising degradedtherapeutic agent may have an undesired effect on the patient, and theporous frit structure as described herein may at least partially filtersuch particulate so as to inhibit potential side effects of degradedtherapeutic agent.

Table 6D shows examples of sizes of therapeutic devices that can beconstructed in accordance with the teachings described herein, so as toprovide a suitable volume of the drug reservoir within the container andsuch devices may comprise many lengths, widths and structures asdescribed herein. For example the frit outside diameter (hereinafter“OD”) can be configured in many ways and may comprise about 1 mm, forexample, or about 0.5 mm. The length of the fit (thickness) may compriseabout 1 mm. The volume of the frit can be, for example, about 0.785 uL,or about 0.196 uL, for example. The volume of the reservoir can be fromabout 0.4 uL to about 160 uL, for example. The volume of the therapeuticdevice can be from about 0.6 uL to about 157 uL, and can be positionedin many ways, for example with a lumen and may comprise a substantiallyfixed volume reservoir or an expandable reservoir. The cross sectionalwidth of the device may correspond to many sizes, for example manyradii, and the radius can be within a range from about 0.3 mm to about3.5 mm, for example. The cross-section width and corresponding diametersof the device can be within a range from about 0.6 mm to about 7 mm. Thelength of the device, including the porous structure, container andretention structure can be many sizes and can be within a range fromabout 2 mm to about 4 mm, for example. The device may comprise asubstantially fixed diameter, or alternatively can be expandable, andmay comprise fixed or expandable retention structures, as describedherein.

TABLE 6D Frit OD (mm) 1 0.5 Frit Length (mm) 1 1 Frit Vol. (uL) 0.7850.19625 Vol Res (uL) 0.4 2 4 8 16 27 31 39 63 110 157 Vol Frit (uL)0.19625 0.19625 0.785 0.785 0.785 0.785 0.785 0.785 0.785 0.785 0.785Vol Device (uL) 0.59625 2.19625 4.785 8.785 16.785 27.785 31.785 39.78563.785 110.785 157.785 Radius squared 0.09 0.3 0.4 0.7 1.3 2.2 2.5 3.25.1 8.8 12.6 Radius (mm) 0.3 0.5 0.6 0.8 1.2 1.5 1.6 1.8 2.3 3.0 3.5 OD(mm) 0.6(4) 1.1(3) 1.2(3) 1.7(3) 2.3(3) 3.0(2) 3.2(2) 3.6(2) 4.5(2)5.9(2) 7.1(2) Dev Length 2.0(6) 2.5(5) 4.0(1) 4.0(1) 4.0(1) 4.0(1)4.0(1) 4.0(1) 4.0(1) 4.0(1) 4.0(1) (mm) (1) Fixed penetration upperlimit (2) May use non simple cylinder design to decrease incisionlength, for example expandable reservoir (3) OD accommodates 1 mmdiameter porous frit structure and satisfies incision length limit (4)Device OD may use a smaller porous frit structure (5) Length reduced todrive OD to accommodate porous frit structure (6) Length reduced todrive OD to accommodate porous frit structure, and Device OD may usesmaller frit

Example 15A Calculation and Measurement of Small Release Rate Profilesas a Model for a Therapeutic Agent Released Through the Porous FritStructure

Studies of the release of fluorescein from reservoirs through porousfrit structures were conducted so as to determine the release of smallmolecule drugs through the porous frit structure. The fluorescein modelshows that the porous fit structures and reservoirs as described hereinare suitable for use with small molecule drug deliver. The releaseprofiles of Avastin™, Lucentis™ and BSA in conjunction with thefluorescein data show that the porous frit structures and reservoirs canbe used for sustained release of many drugs, molecules and therapeuticagents of many molecular weights and sizes.

FIG. 25A shows cumulative release for fluorescein through a 0.2 mediagrade porous frit structure. The experiment used: 2 mg/mL Fluoresceinsodium; Frit #2 (0.031×0.049″, media grade 0.2 um, 316L SS, MottCorporation); Machined polycarbonate surrogate with screw; 37C. Thefluorescein samples were assayed by UV absorbance at 492 nm with a platereader. The determined RRI based on measurements is 0.02, consistentwith the model for release of the therapeutic agents as describedherein.

FIG. 25A-1 shows cumulative release to about 90 days for fluoresceinthrough a 0.2 media grade porous fit structure as in FIG. 25A. The meanRRI based upon the first four data points was 0.02 mm. The mean RRI torelease for 90 days (excluding the first point) is 0.026 mm. These datashow stability of the rate of release and that the porous frit structurecan be used for small molecule delivery or large molecule delivery, orcombinations thereof.

FIG. 25B shows rate of release as in FIG. 25A. The release rate datashow a rate of release from about 1.0 ug per day to about 1.8 ug perday. Although the initial release rate at the first day is slightlylower than subsequent rates, the rate of release is sufficiently high toprovide therapeutic effect in accordance with the drug release model.Although there can be an initial period of about a day for the releaserate profile to develop, possibly related to wetting of theinterconnecting channels of the porous structure, the release rateprofile corresponds substantially to the release rate index (RRI) of0.02. Based on the teachings described herein, a person of ordinaryskill in the art could determine the release rate profile withadditional data for an extended time of at least about one month, forexample at least about three months, six months or more, so as todetermine the release rate profile for an extended time.

FIG. 25B-1 shows rate of release as in FIG. 25A-1.

Example 15B Measured Release Rate Profiles for Lucentis™ Through thePorous Frit Structures

The experiments used: 10 mg/mL Lucentis™; Machined poly(methylmethacrylate) surrogate with screw; and a Reservoir Volume 30 uL; 37C.All porous frit structures are 316L SS, Mott Corporation. Data shown aremeasured data from all devices except for a few samples that showedeither bubble growth or low receiver volume.

Table 6E shows results for 39 out of 48 devices were included in thetable and graphs shown below. The data from the in vitro studies shownin Table 6E show that Lucentis™ can be delivered with the device havingporous frit structure. The diameter ranged from 0.031″ to 0.038″, andthe length ranged from 0.029 to 0.049. The media grade ranged from 0.1to 0.3, and the RRI ranged from 0.014 to 0.090. The data show very lowvariability suitable in in vivo human treatment, with the % CV below 10%in all instances, and less than 3% for four of five deviceconfigurations measured.

Although some of the measurements were excluded, this exclusion isappropriate and associated with in vitro testing conditions that differsubstantially from the in vivo model. Five devices were excluded due tobubble growth (10%), and four were excluded due to receiver volumeissues at one timepoint for that device (8%). The latter can be anexperimental error associated with the volume of the receiver below theassumed value due to evaporation from inadequately sealed vials or dueto pipetting error. In some instances the in vitro experimental testapparatus can be sensitive to bubble formation that may differsubstantially from the in vivo model as the living eye can resorb oxygenfrom the therapeutic devices. Bubbles can form as receiver fluid isheated to 37° C. and gas concentrations are greater than theirsolubilities at 37° C. To minimize the occurrence of bubble formation,receiver solutions were degassed before insertion of the devices. Theseexperimental in vitro studies suggest that degassing of samples can behelpful with the in vitro assays.

TABLE 6E Frit Media Dimensions Grade RRI Number of Dia Length (μm) (mm)% CV Replicates 0.038″ 0.029″ 0.3 0.090 2.1% 6 0.038″ 0.029″ 0.2 0.0612.8% 14 0.038″ 0.029″ 0.1 0.039 2.3% 5 0.031″ 0.049″ 0.2 0.021 9.9% 120.031″ 0.049″ 0.1 0.014 2.5% 2

FIG. 25C shows cumulative release to about thirty days for Lucentis™through a 0.2 media grade porous frit structure having a diameter of0.038 in and a length (thickness) of 0.029, corresponding to a releaserate of 0.061 as shown in the second row of Table 6E.

FIG. 25D shows rates of release of the devices as in FIG. 25C.

FIG. 25E shows cumulative release to about thirty days for Lucentis™ for30 uL devices having a RRI's from about 0.090 to about 0.015.

FIG. 25F shows rates of release of the devices as in FIG. 25E.

FIG. 25E1 and 25F1 show an update of Lucentis drug release studies inFIGS. 25E and 25F, respectively, measured up to 6 months. Data for twodevices having the fastest releasing RCEs ends prior to 6 months whenthe therapeutic agent has been substantially depleted.

These above experimentally measured data show stable release of theLucentis™ for 30 days for a wide range of frit diameters, thicknessesand media grades consistent with the release rate model of the porousstructure and reservoir as described herein. For example, the mediagrade, thickness, diameter and reservoir volume can be tuned to providesustained release for a predetermined period of time above apredetermined targeted minimum inhibitory concentration. When combinedwith the Avastin™ and Fluorescein data, these data show that stablerelease can be achieved for extended times for many therapeutic agentsconsistent with the release model as described herein.

Example 16 Scanning Electron Micrographs of Porous Frit Structures

FIGS. 26A and 26B show scanning electron microscope images fromfractured edges of porous fit structures of 0.2 media grade and 0.5media grade porous material, respectively. The commercially availablesamples were obtained from Mott Corporation and comprised 316L stainlesssteel. The samples were mechanically fractured so as to show the porousstructure and interconnecting channels within the material to releasethe therapeutic agent. The micrograph images show a plurality ofinterconnecting channels disposed between openings of the first surfaceand openings of the second surface.

FIGS. 27A and 27B show scanning electron microscope images from surfacesof porous fit structures of media grade of 0.2 and 0.5, respectively,from the samples of FIGS. 26A and 26B. The images show a plurality ofopenings on the surface connected with interconnecting channels as inFIGS. 26A and 26B.

Example 17 Porous Frit Structure Mechanical Flow Testing to IdentifyPorous Frit Structures Suitable for Use with Therapeutic Agent DeliveryDevices

The relative characteristics of sample elements can be determined bysubjecting the fit to a number of mechanical tests, including but notlimited to pressure decay and flow. These tests can be combined withdrug release rate information, for example the RRI, so as to determinethe release profile of the devices. These tests can be used with theporous structure positioned on the therapeutic device, so as to quantifyflow through the porous structure of the device and determine suitableof the porous structure. Similar tests can be used to quantify theporous structure prior to mounting on the therapeutic device. At leastsome of the therapeutic devices can be evaluated with the gas flow ofthe porous structure mounted on a partially assembled therapeuticdevice, for example as a quality control check In some embodiments, theflow test can be performed on the partially assembled or substantiallyassembled therapeutic device prior to insertion of the therapeutic agentinto the reservoir and prior to insertion into the patient, so as toensure that the porous structure is suitable for release of thetherapeutic agent and affixed to the device, for example a support ofthe therapeutic device.

These tests may utilize a variety of working fluids, but will mostlikely use a readily available gas such as air or nitrogen. To date,flow and pressure decay tests have been used to identify different fritcharacteristics that may be correlated to other test results such aschemical or pharmacologic performance.

Fixturing

Each of the test methods above may use a mechanical connection of thetest specimen to the test hardware and a number of techniques have beenexplored and employed. These fixtures include a both a means of reliablysecuring the specimen (such as heat recoverable tubing, elastic tubing,press fits into relatively rigid components, etc.) and a means ofcoupling (such as a Luer, barbed fitting, quick connect coupling, etc.)that allow convenient and repeatable attachment to the test hardware.

Test Hardware

Each of the desired tests can be developed using commercially availablesolutions, or by assembling readily available instrumentation to createa custom test arrangement. Again, both of these approaches have beenevaluated. A working system will consist of a means for connecting atest specimen, a controllable source (usually, but not limited topressure), a manometer (or other pressure measurement device), and oneor more transducers (pressure, flow, etc.) used to measure the testconditions and/or gather data for further analysis.

Example 17A Pressure Decay Test to Identify Porous Structures Suitablefor Use with Therapeutic Drug Delivery Devices

FIG. 28 shows a pressure decay test and test apparatus for use with aporous structure so as to identify porous frit structures suitable foruse with therapeutic devices in accordance with embodiments describedherein.

One method of pressure decay testing is performed with the hardwareshown schematically in FIG. 28. An initial pressure is applied to thesystem by an outside source such as a syringe, compressed air,compressed nitrogen, etc. The manometer may be configured to displaysimply the source gage pressure, or the actual differential pressureacross the specimen. One side of the fixtured specimen is normally opento atmosphere, creating a pressure which will decay at a rate determinedby the properties of the frit being tested. The instantaneous pressuremay be measured by a pressure transducer that converts and supplies asignal to a data acquisition module (DAQ) that transfers data to acomputer. The rate of pressure drop is then recorded and can be used forcomparison to the performance of other frits or an acceptabilityrequirement/specification. This comparison may be made by grosslycomparing the pressure at a given time, or by directly comparing theoutput pressure decay curves.

An example test procedure would pressurize the system too slightlygreater than 400 mmHg as displayed by the manometer. The computer andDAQ are configured to begin data acquisition as the pressure drops below400 mmHg, and a data point is taken approximately every 0.109 seconds.While the test can be stopped at any time, it is likely that standarddiscreet points along the course of pressure decay data would beselected so as to allow direct comparison of fit flow performance (e.g.time for decay from 400 mmHg to 300 mmHg, and from 400 mmHg to 200mmHg.)

Example 17B Pressure Decay Test to Identify Porous Structures Suitablefor Use with Therapeutic Drug Delivery Devices

FIG. 29 shows a pressure flow test and test apparatus suitable for usewith a porous structure so as to identify porous frit structuressuitable for use with therapeutic devices in accordance with embodimentsdescribed herein.

Using a similar hardware set-up, flow thru the test specimen can also becharacterized. In this test, the source pressure is constantly regulatedto a known pressure and the flow of a working fluid is allowed to flowthru a mass flow meter and then thru the fixtured test fit. As in thepressure decay test, the specific characteristics of the frit determinethat rate at which the working fluid will flow through the system. Foradditional accuracy, pressure at the otherwise open end of the fixturetest frit may be regulated to control the backpressure, and thereforethe pressure drop across the specimen.

Flow testing may have advantages over pressure decay testing due to theinstantaneous nature of the method. Rather than waiting for the pressureto drop, the flow thru a sample should stabilize quickly enablingtesting of large number of samples to be performed in rapid fashion.

In an example test procedure, a regulated compressed cylinder wouldsupply the system with a constant source pressure of 30 psig and aconstant back pressure of 1 psig. The test fluid would flow through thetest frit at a characteristic rate (which is dependent on the pressure,but is expected to be in the 10-500 sccm range) as measured by the massflow meter.

Example 17C Determination of Therapeutic Release Rate Based on Gas Flow

Table 7 shows a table that can be used to determine release oftherapeutic agent, for example the RRI, based on the flow of a gas suchas oxygen or nitrogen through the porous structure. The flow through theporous structure can be measured with a decay time of the gas pressure,for example with the flow rate across the porous structure with apressure drop across the porous fit structure, as described herein. Theflow rate and RRI can be determined based on the media grade of thematerial, for example as commercially available media grade materialavailable from Mott Corp. The therapeutic agent can be measured throughthe porous structure, or a similar test molecule. The initialmeasurements measured the RRI for Avastin™ with the porous fritstructures shown. Based on the teachings described herein, a person ofordinary skill in the art can conduct experiments to determineempirically the correspondence of flow rate with a gas to the releaserate of the therapeutic agent.

TABLE 7 Media Length 200 Grade O.D.(in.) (in.) RRI Flow 300 Decay Decay0.2 0.031 0.049 0.019 106 256 0.2 0.038 0.029 0.034 0.1 0.038 0.0290.014 81 201 0.2 0.038 0.029 0.033 31 78

The above partially populated table shows the amount and nature of fitdata that can collected. It is contemplated to use some form ofnon-destructive testing (i.e. not drug release testing) so as to enable:

a) QC receiving inspection testing of fritsb) QC final device assembly testing

One of ordinary skill can demonstrate a correlation between one or more“flow” tests and the actual drug release testing which relies ondiffusion rather than forced gas flow. The data suggests that flowtesting of fits can be both repeatable and falls in line withexpectations.

Preliminary testing also indicates that the test for the frit alone canbe substantially similar to the frit as an assembled device.

Example 18 Determination of Minimum In Vivo Inhibitory Concentration ofLucentis™ in Humans

Although administration of the standard dose of Lucentis™ (500 μg) viadirect intravitreal injection has been shown to be effective in reducingsymptoms of patients suffering from wet AMD, the below clinical studiesindicate that a lower concentration can be used to treat wet AMD. Adevice as described herein can be used to treat AMD with a minimuminhibitory concentration in vivo in human patients (hereinafter “MIC”)with a smaller amount than corresponds to the 500 μg monthly bolusinjection. For example, 5 ug Lucentis™ injections can be administered soas to obtain a concentration profiles in situ in humans in accordancewith Table 4D and FIG. 19A above.

The study was designed to detect quickly a positive response toLucentis™ treatment. A reduction of retinal thickness is an indicator ofpositive response to Lucentis™ therapy and a marker of drug effect thatcan be used to quickly identify a positive effect of drug treatment. Thereduction in retinal thickness corresponds to subsequent improvement invision. Hence, the low dose MIC study assessed the condition of retinalthickness both before and after patient's exposure to low dose bolusadministration of Lucentis™, so as to determine the MIC.

OCT (Optical Coherence Tomography) imaging was used to assess thecondition of the region of the macula at the back surface of the treatedeye. The OCT technique relies on the measurement of certain propertiesof light (e.g. echo time, intensity of reflection) that has beendirected at the area of study and can measure very small amounts ofreflected light. Because these cellular features are essentiallytransparent it is possible to use OCT methodology to generate threedimensional representations of the area.

The anatomical region of patients suffering from wet AMD typicallyinvolves disturbances to the structural make-up of the various cellularlayers of the back surface of the eye, notably including areas ofretinal thickening often involving accumulations of subretinal fluid. Inmore advanced stages these areas of fluid accumulation often involvecyst-like formations easily evaluated via OCT.

The OCT images generated in the study enabled of various types ofassessments to be made regarding the condition of the anatomical regionof interest. One type of OCT image comprises a topographic map of theentire region of the macula. This image type is referred to as the“macular cube”. The macular cube OCT images are typically displayed ascolor images and in the case of the macular cube the image provides anindication of overall topography of the disease/lesion location. Thesemacular cube images were used identify regions of the macular ofinterest.

The regions of interest were analyzed with a two dimensionalrepresentation of the cross section of the retinal wall at onelongitudinal scan location of the OCT image. In these “OCT scan” imagesis it possible to interrogate very local areas of interest morespecifically. The OCT scans were carefully selected to directly comparethe thickness and anatomical structure of specific sites within alesion, pre and post treatment, for the purpose of assessing the effectof injected drug including a reduction in sub-retinal fluid.

Macular cube images and OCT scan images were measured before and afterLucentis™ treatment for each patient enrolled in the study. The OCTimages were measured the day after injection and at 2-3 days postinjection. An ophthalmologist reviewed the OCT images from the patientsenrolled in the study, and patients were considered to have a respondedto Lucentis™ treatment when the OCT scans showed a decrease in size ofthe lesion from one or more of the post-injection examinations.

FIG. 30A-1 shows an example of an OCT macular cube OCT image used toidentify a region of interest (black arrow) and determine the responseto treatment.

FIGS. 30B-1, 30B-2 and 30B-3 shows an example of a series of OCT scanimages measured at pre-injection, one day post-injection and one weekpost-injection, respectively of sections of the region of interest.

Table 8 shows the results for 9 patients enrolled in the study. Thepatients received doses from 5 to 20 ug, corresponding to initialLucentis™ concentrations in the vitreous from 1 to 4 ug/ml. Based on theabove criteria, a positive response was identified in all 9 patients. Inat least some instances with the 5 um injection, the decrease in size ofthe lesion was noted approximately 2-4 days post-op, and the decreasewas substantially attenuated by one week post-op, consistent with theapproximately 9 day in vivo half-life of Lucentis™. These data indicatedthat the MIC for a sustained release device may be approximately 1 ugper ml or less. As the therapeutic agent may have a cumulative effect,the MIC can be lower for a sustained release as described herein thanthe bolus injection described with reference to the MIC study. Furtherstudies can be conducted by one or ordinary skill in the based on theteachings described herein to determine empirically the MIC for asustained release device and cumulative effect of the drug over the timeof release.

TABLE XX Patient # 1 2 3 4 5 6 7 8 9 Lowest Dose 10 20 20 5 20 5 5 5 5Administered (μg) Estimated Initial 2 4 4 1 4 1 1 1 1 Drug Conc. inVitreous (μg/mL) Treatment Yes Yes Yes Yes Yes Yes Yes Yes Yes EffectObserved?

FIGS. 31A and 31B show experimental implantation of therapeutic devicesinto the pars plana region 25 of a rabbit eye. Approximately 4prototypes of the device as shown in FIG. 7A to 7B-6F were implantedinto the rabbit eye. The retention structure of each devices comprised asubstantially clear and transparent oval flange 122 positioned on thesclera under the conjunctiva. The clear and transparent flange 122permits visualization of the interface of the scleral incision andnarrow portion 120N of the retention structure, such that sealing of theretention structure to the sclera can be evaluation. The retentionstructure of each device also comprise an access port 180 having asubstantially clear penetrable barrier 184 so as to permit dark fieldvisualization of the location of the implanted device. The narrowportion 120N of the retention structure is disposed under thetransparent flange, and barrier 160 has the oval shape so to define thenarrow portion of the retention structure.

These studies showed that the retention structure comprising the ovalflange and oval narrow portion can seal the incision formed in thesclera and permit dark field visualization of the implanted device. Thedevice can be implanted temporally in the patient, for examplesuperior/temporally or inferior/temporally such that the implant can bedisposed temporally and under the eyelid so as to have a minimal effecton vision and appearance of the patient.

FIG. 32A shows the concentration profile of monthly bolus injections of2 mg of ranibizumab directly into the vitreous humor as compared with aninjection into the device 100 comprising 4.5 mg ranibizumab such that2.5 mg of ranibizumab are stored in the device and 2 mg of ranibizumabare injected into the eye through the porous structure 150. Manyconcentrations of therapeutic agent can be combined with many reservoirvolumes and many RRIs to provide the 2.0 mg injected through the deviceand the 2.5 mg retained in the device, based on the teachings describedherein. The device parameters correspond to a substantially constant 25uL reservoir chamber volume of the container of device 100, and an RRIof about 0.02 as described above. The modeling is based on flushing ofthe device with the injector into the vitreous humor of the eye asdescribed above. The diffusion constants and half-life of Lucentis inthe vitreous humor correspond to those described above such as thehalf-life in the vitreous of about nine days and a vitreous volume ofabout 4.5 ml.

The monthly bolus injections of 2 mg correspond to 50 uL injections of40 mg/ml ranibizumab as described above and as under FDA approvedclinical study by Genentech. The monthly bolus injections provide aninitial vitreous concentration of about 440 ug/ml that decrease to about40 ug/ml. The second monthly bolus injection provides an initialvitreous concentration of about 480 ug/ml based on the combination ofthe ranibizumab in the vitreous prior to the second injection and theamount 440 ug provided with the bolus injection.

The 4.5 mg injection into the device provides an initial concentrationof about 440 ug/ml based on the 2.0 mg injected through the device 100and the 2.5 mg retained in the reservoir container of device 100. Manyconcentrations of therapeutic agent can be combined with many reservoirvolumes and many RRIs to provide the 2.0 mg injected through the deviceand the 2.5 mg retained in the device, based on the teachings describedherein. Based on the half life of ranibizumab in the vitreous humor ofthe eye and the 440 ug/ml initial concentration, ranibizumab is removedfrom the eye with amounts greater than the rate of release of thetherapeutic device 100, such that the initial 440 ug/ml vitreousconcentration provided by the bolus injection through device 100corresponds to a peak concentration of the ranibizumab concentrationprofile. This unexpected result can allow a bolus injection into thetherapeutic device up to an established safe peak concentration to becombined with the injection into the therapeutic device withoutexceeding the established peak safety concentration when providingrelease of therapeutic amounts for an extended time.

FIG. 32B shows the concentration profile of monthly bolus injections of2 mg of ranibizumab directly into the vitreous humor as compared with aplurality of injections into the device 100 comprising 4.5 mgranibizumab such that 2.5 mg of ranibizumab are stored in the device and2 mg of ranibizumab are injected into the eye through the porousstructure 150. Many concentrations of therapeutic agent can be combinedwith many reservoir volumes and many RRIs to provide the 2.0 mg injectedthrough the device and the 2.5 mg retained in the device, based on theteachings described herein. The bolus injections directly into thevitreous correspond substantially to those shown above. The firstinjection at time 0 into the device 100 corresponds substantially to theinjection shown in FIG. 32A. The second injection of the plurality showsamount of therapeutic agent 110 comprising ranibizumab to provide a peakconcentration of about 600 ug/ml. The additional concentration maycomprise ranibizumab of the first injection stored in the therapeuticdevice 100 when the second injection of 4.5 mg into the device isperformed such that the stored amount is passed through the porousstructure. The third of the plurality of injections shows a similarpeak. These calculations assumed no mixing of the second injection withthe first injection, and 100% fill efficiency. Based on the teachingsdescribed herein, a person of ordinary skill in the art can adjust thesecond amount injected based on one or more of the amount of thetherapeutic agent 110 comprising ranibizumab in device 100 from thefirst injection when the second injection is performed, the fillingefficiency, the percent mixing, or the efficiency of exchange when used.

FIG. 32C shows the plurality of ranibizumab injections of 4.5 mg and themonthly bolus injections of 2 mg as in FIG. 32B as compared with monthlybolus injections of 0.5 mg of commercially available and approvedLucentis™. Many concentrations of therapeutic agent can be combined withmany reservoir volumes and many RRIs to provide the 2.0 mg injectedthrough the device and the 2.5 mg retained in the device, based on theteachings described herein. These data show that the vitreousconcentration profile of ranibizumab from device 100 can be maintainedwithin the therapeutic window of bolus injections and provide extendedrelease for at least about 30 days, for example at least about 120 days.

FIGS. 32D and 32E show injections with amounts into the device 100 andbolus injections similar to FIGS. 32A to 32C, in which the injectionsare performed at 6 months. Many concentrations of therapeutic agent canbe combined with many reservoir volumes and many RRIs to provide the 2.0mg injected through the device and the 2.5 mg retained in the device,based on the teachings described herein. These data show that thevitreous concentration profile of ranibizumab from device 100 can bemaintained within the therapeutic window of bolus injections and provideextended release for at least about 30 days, for example at least about180 days. Similar adjustments can be made to the second injection intothe therapeutic device, and injections thereafter, as described above tomaintain the vitreous concentration profile within the peak profile ofthe injection.

FIGS. 33A and 33A1 show a side cross sectional view and a top view,respectively, of therapeutic device 100 for placement substantiallybetween the conjunctiva and the sclera. The therapeutic agent 110 asdescribed herein can be injected when device 100 is implanted. Thetherapeutic device 100 comprises container 130 as described hereinhaving penetrable barrier 184 as described herein disposed on an uppersurface for placement against the conjunctiva. An elongate structure 172is coupled to container 130. Elongate structure 172 comprises a channel174 extending from a first opening coupled to the chamber of thecontainer to a second opening 176 on a distal end of the elongatestructure. The porous structure 150 as described herein is located onthe elongate structure 172 and coupled to the container 130 so as torelease therapeutic agent for an extended period, and a retentionstructure 120 comprising an extension protruding outward from thecontainer 130 to couple to the sclera and the conjunctiva. The containermay comprise barrier 160 as described herein that defines at least aportion of the reservoir, and the container may comprise a width, forexample a diameter. The barrier 160 may comprise a rigid material, forexample rigid silicone or rigid rubber, or other material as describedherein, such that the volume of the chamber of container 130 comprises asubstantially constant volume as described herein. Alternatively or incombination, barrier 160 may comprise a soft material, for example whenthe chamber size is decreased such that the volume can be substantiallyconstant with the decreased chamber size. A soft barrier material can becombined with a rigid material, for example a support material. Thediameter can be sized within a range, for example within a range fromabout 1 to about 8 mm, for example within a range from about 2 to 6 mmand can be about 3 mm, for example.

The container may be coupled to elongate structure 172 sized, and theelongate structure having a length sized so as to extend from theconjunctive to the vitreous to release the therapeutic agent into thevitreous. The length can be sized within a range, for example within arange from about 2 to about 14 mm, for example within a range from about4 to 10 mm and can be about 7 mm, for example. The penetrable barriermay comprise a septum disposed on a proximal end of the container, inwhich the septum comprises a barrier that can be penetrated with a sharpobject such as a needle for injection of the therapeutic agent. Theporous structure may comprise a cross sectional area sized to releasethe therapeutic agent for the extended period. The elongate structure172 can be located near a center of the container 130, or may beeccentric to the center.

The elongate structure 172 can be inserted into the sclera at the parsplana region as described herein.

The barrier 160 can have a shape profile for placement between theconjunctiva and sclera. The lower surface can be shaped to contact thesclera and may comprise a concave shape such as a concave spherical ortoric surface. The upper surface can be shaped to contact theconjunctivae and may comprise a convex shape such as a convex sphericalor toric surface. The barrier 160 may comprise an oval, an elliptical,or a circular shape when implanted and viewed from above, and theelongate structure 172 can be centered or eccentric to the ellipse. Whenimplanted the long dimension of the oval can be aligned so as to extendalong a circumference of the pars plana.

The cross sectional diameter of the elongate structure 172 can be sizedto decrease the invasiveness of device 100, and may comprise a diameterof no more than about 1 mm, for example no more than about 0.5 mm, forexample no more than about 0.25 mm such that the penetrate sclera sealssubstantially when elongate structure 172 is removed and the eye canseal itself upon removal of elongate structure 172. The elongatestructure 172 may comprise a needle, and channel 174 may comprise alumen of the needle, for example a 30 Gauge needle.

The porous structure 150 may comprise a first side a described hereincoupled to the reservoir and a second side to couple to the vitreous.The first side may comprise a first area 150 as described herein and thesecond side may comprise a second area. The porous structure maycomprise a thickness as described herein. The porous structure manycomprise a diameter. The porous structure may comprise a release rateindex, and the chamber of container 130 that defines the volume ofreservoir 140 can be sized such that the porous structure and the volumeare tuned to receive and amount of therapeutic agent injected with avolume of formulation of therapeutic agent and tuned to releasetherapeutic amounts for an extended time. Many release rate mechanismsas described herein can be used to tune the release rate and volume tothe quantity of therapeutic agent injected as described herein.

The volume of the reservoir 140 defined by the chamber of the containermay comprise from about 5 uL to about 2000 uL of therapeutic agent, orfor example from about 10 uL to about 200 uL of therapeutic agent.

The porous structure may comprise a needle stop that limits penetrationof the needle. The porous structure may comprise a plurality of channelsconfigured for the extended release of the therapeutic agent. The porousstructure may comprise a rigid sintered material having characteristicssuitable for the sustained release of the material.

FIG. 33A2 shows the therapeutic device 100 implanted with the reservoirbetween the conjunctiva and the sclera, such that elongate structure 172extends through the sclera to couple the reservoir chamber to thevitreous humor. When implanted, the porous structure 150 can be locatedin the vitreous humor, or located between the conjunctiva and sclera, ormay extend through the sclera, or combinations thereof.

FIG. 33B shows the porous structure 150 of therapeutic device 100located in channel 174 near the opening to the chamber of the container130. The porous structure can extend substantially along the length ofelongate structure 172.

FIG. 33C shows the porous structure 150 located within the chamber ofcontainer 150 and coupled to the first opening of the elongate structure172 so as to provide the release rate profile. The porous structure cancover the opening of elongate structure 172 such that therapeuticamounts are released for the extended time as described herein.

FIG. 33D shows a plurality of injection ports spaced apart so as toinject and exchange the liquid of chamber of the container 130 andinject the therapeutic agent into the reservoir chamber of the container130. The penetrable barrier 184 may comprise a first penetrable barrierlocated in a first access port formed in the barrier 160 and a secondpenetrable barrier located in a second access port formed in the barrier160, and the first barrier can be separated from the second barrier byat least about 1 mm.

The injector 701 as described above can be configured to coupled to thereservoir placed between the conjunctiva and the sclera as describeherein. The injector 701 can be coupled to a double lumen needle 189Lsuch that a second lumen 189B injects therapeutic agent 110 from achamber 702C into device 100, and the first lumen can be spaced apartfrom the second lumen with the distance extending therebetween sized toposition the first lumen in the first septum as described above and thesecond lumen in the second septum as described above. The secondcontainer 703C can be coupled to a first lumen 189A that extends to thechamber of the reservoir container and receives liquid from device 100,such that liquid of device 100 is exchanged when the chamber of thereservoir container is positioned between the conjunctiva and thesclera. The switching valve 703V to exchange an intended amount ofliquid and an intended amount of the formulation the therapeutic agent110, and inject an intended amount of therapeutic agent injected intodevice 100, for example such that a bolus amount of therapeutic agentcan be injected from device 100 as described above. A portion of theformulation of therapeutic agent injected into device 100 can beretained in device 100 for release for an extended time.

FIG. 34 shows the elongate structure 172 coupled to the container 130away from the center of container 130 and near and located near an endof the container.

Materials for Porous Structures and Housing

The material of the housing and porous structure may comprise a materialhaving a decreased interaction with the therapeutic agent such asranibizumab.

FIG. 35 shows stability data for a formulation of Lucentis that can beused to identify materials for porous frit structures. These data showthe stability of Lucentis over time for containers having materials suchas stainless steel, Ti, PMMA and silicone. These data were measured withion exchange chromatography, and can be measured in accordance withpublished references describing Mab patterns on SCX-10 column. The datawere measured in accordance with references on the Dionex website, suchas:

Development data by the Manufacturer Dionex Corp.

Title: MAbPac SCX-10 Column for Monoclonal Antibody Variant Analysis

http://www.dionex.com/en-us/webdocs/87008-DS-MAbPac-SCX-10-Column-20Aug2010-LPN2567-03.pdf

Table VV shows recovery and stability of Lucentis with materials thatcan be used for porous structure 150 as described herein. Additionaltesting of additional materials can be performed, for example with oneor more ceramic materials. Table VV shows Ion Exchange Chromatography ofLucentis with Device Components in Accelerated Stability for Lucentis 1mg/mL pH 7.3 (PBS) for 35 days. Recovery was corrected for theevaporated water lost during the stability (8.0%). Data was veryrepeatable. 3 injections, area integration within +8% RSD.

TABLE VV RECOVERY AND STABILITY OF LUCENTIS WITH MATERIALS FOR POROUSSTRUCTURES Component Study 37° C. 35 Days Sample % Recovery Average %Purity Control 37° C. 98.1 87.3 Stainless 37° C. 89.5 68.8 Titanium 37°C. 96.2 80.8 PMMA 37° C. 97.8 88.2 Silicone 37° C. 98.0 87.3

The above data indicate that Titanium (Ti), acrylate polymer such asPMMA, or siloxane such as silicone may provide increased stability ascompared to stainless steel in at least some instances. Similar testingcan be performed on additional materials as described herein, forexample with one or more ceramic materials.

Based on the teachings described herein, a person of ordinary skill inthe art can conduct experiments to determine empirically the releaserate index of the porous structure 150 for the material identified, suchas titanium. For example, gas flow data measured as described hereinhave shown that for a given material such as stainless steel, mediagrade and porosity, the gas flow data such as flow rate or decay timecan be correlated with the release rate index, such that a porousstructure 150 can be identified based on material, gas flow data, mediagrade and porosity. The correlation between gas flow data and releaserate index for a sintered porous structure having a known material,media grade and porosity can be used to determine the release rate indexof the porous structure.

The porous structure 150 can be combined with amounts of therapeuticagent, for example ranibizumab, so as to provide extended release with aplurality of injections for an extended time post each injection.

Amounts of Ranibizumab

Based on the teachings described herein, amounts of ranibizumab can beinjected into device 100 in many ways so as to provide an intendedamount of therapeutic agent at or above a target amount for an extendedtime, such as 3 months or 6 months, for example. The device 100 maycomprise the subjconctival device, for example, or may comprise a devicehaving the reservoir located substantially in the vitreous. Based on theteachings described herein, the target amount of release at an extendedtime post injection, for example 3 months or 6 months, can be used todetermine the amount of therapeutic agent. The reservoir can be sizedbased on the concentration of formulation and amount of therapeuticagent, and the RRI determined based on the amount released at theextended time post injection and the concentration of formulation.

Table WW provides examples of amounts of therapeutic agents that can beinjected into a reservoir of the therapeutic device, and amounts of thetherapeutic agent ranibizumab that can be released when the reservoirand porous structure are tuned to receive the amount of therapeuticagent. Table WW shows amounts of ranibizumab therapeutic agent fromabout 0.1 mg to about 30 mg. These amounts can be combined with overinjection above the amount of reservoir capacity to release a bolus andwith exchange as described herein, for example when the amount of TableWW corresponds to the reservoir capacity of the therapeutic device 100.

TABLE WW Amounts of ranibizumab therapeutic agent released at 90 and 180days with RRI tuned to reservoir volume and concentration of therapeuticagent. rate at 90 days rate at 180 days rri mg protein ug/day ug/day0.01 0.10 0.4 0.2 0.02 0.10 0.4 0.1 0.04 0.10 0.2 0.0 0.06 0.10 0.0 0.00.08 0.10 0.0 0.0 0.01 0.15 0.5 0.3 0.02 0.15 0.6 0.2 0.04 0.15 0.4 0.10.06 0.15 0.2 0.0 0.08 0.15 0.1 0.0 0.01 0.20 0.6 0.4 0.02 0.20 0.8 0.40.04 0.20 0.7 0.2 0.06 0.20 0.5 0.0 0.08 0.20 0.3 0.0 0.01 0.25 0.6 0.50.02 0.25 0.9 0.5 0.04 0.25 1.0 0.3 0.06 0.25 0.8 0.1 0.08 0.25 0.6 0.00.01 0.30 0.7 0.5 0.02 0.30 1.0 0.6 0.04 0.30 1.2 0.4 0.06 0.30 1.1 0.20.08 0.30 0.9 0.1 0.01 0.40 0.7 0.6 0.02 0.40 1.2 0.8 0.04 0.40 1.6 0.70.06 0.40 1.6 0.5 0.08 0.40 1.5 0.3 0.01 0.50 0.7 0.6 0.02 0.50 1.3 0.90.04 0.50 1.9 1.0 0.06 0.50 2.0 0.8 0.08 0.50 2.0 0.6 0.01 0.40 1.6 0.70.01 0.60 2.1 1.2 0.01 0.80 2.3 1.6 0.01 1.00 2.5 1.9 0.01 1.20 2.7 2.10.01 1.60 2.8 2.3 0.01 2.00 3.0 2.5 0.02 0.40 1.5 0.3 0.02 0.60 2.5 0.90.02 0.80 3.2 1.5 0.02 1.00 3.7 2.0 0.02 1.20 4.1 2.5 0.02 1.60 4.7 3.30.02 2.00 5.1 3.7 0.04 0.40 0.6 0.0 0.04 0.60 1.7 0.2 0.04 0.80 2.9 0.60.04 1.00 4.0 1.1 0.04 1.20 4.9 1.7 0.04 1.60 6.4 2.9 0.04 2.00 7.4 4.00.06 0.40 0.2 0.0 0.06 0.60 0.9 0.0 0.06 0.80 2.0 0.2 0.06 1.00 3.2 0.50.06 1.20 4.4 0.9 0.06 1.60 6.5 2.0 0.06 2.00 8.2 3.2 0.08 0.40 0.1 0.00.08 0.60 0.4 0.0 0.08 0.80 1.2 0.1 0.08 1.00 2.3 0.2 0.08 1.20 3.5 0.40.08 1.60 5.8 1.2 0.08 2.00 8.0 2.3 0.01 1.00 4.0 1.8 0.02 1.00 3.6 0.80.04 1.00 1.5 0.1 0.06 1.00 0.5 0.0 0.08 1.00 0.1 0.0 0.01 1.50 5.1 3.10.02 1.50 6.1 2.2 0.04 1.50 4.3 0.5 0.06 1.50 2.3 0.1 0.08 1.50 1.1 0.00.01 2.00 5.9 4.0 0.02 2.00 7.9 3.6 0.04 2.00 7.3 1.5 0.06 2.00 5.0 0.50.08 2.00 3.1 0.1 0.01 2.50 6.3 4.6 0.02 2.50 9.3 5.0 0.04 2.50 10.0 2.90.06 2.50 8.0 1.2 0.08 2.50 5.7 0.5 0.01 3.00 6.7 5.1 0.02 3.00 10.3 6.10.04 3.00 12.3 4.3 0.06 3.00 10.9 2.3 0.08 3.00 8.7 1.1 0.01 4.00 7.15.9 0.02 4.00 11.7 7.9 0.04 4.00 15.9 7.3 0.06 4.00 16.1 5.0 0.08 4.0014.6 3.1 0.01 5.00 7.4 6.3 0.02 5.00 12.7 9.3 0.04 5.00 18.6 10.0 0.065.00 20.4 8.0 0.08 5.00 19.9 5.7 0.01 2.00 7.9 3.6 0.01 3.00 10.3 6.10.01 4.00 11.7 7.9 0.01 5.00 12.7 9.3 0.01 6.00 13.3 10.3 0.01 8.00 14.211.7 0.01 10.00 14.8 12.7 0.02 2.00 7.3 1.5 0.02 3.00 12.3 4.3 0.02 4.0015.9 7.3 0.02 5.00 18.6 10.0 0.02 6.00 20.6 12.3 0.02 8.00 23.4 15.90.02 10.00 25.3 18.6 0.04 2.00 3.1 0.1 0.04 3.00 8.7 1.1 0.04 4.00 14.63.1 0.04 5.00 19.9 5.7 0.04 6.00 24.5 8.7 0.04 8.00 31.8 14.6 0.04 10.0037.1 19.9 0.06 2.00 1.0 0.0 0.06 3.00 4.6 0.2 0.06 4.00 10.1 1.0 0.065.00 16.0 2.5 0.06 6.00 21.9 4.6 0.06 8.00 32.3 10.1 0.06 10.00 40.816.0 0.08 2.00 0.3 0.0 0.08 3.00 2.2 0.0 0.08 4.00 6.2 0.3 0.08 5.0011.5 1.0 0.08 6.00 17.4 2.2 0.08 8.00 29.2 6.2 0.08 10.00 39.8 11.5 0.014.00 15.9 7.3 0.01 6.00 20.6 12.3 0.01 8.00 23.4 15.9 0.01 10.00 25.318.6 0.01 12.00 26.7 20.6 0.01 16.00 28.5 23.4 0.01 20.00 29.6 25.3 0.024.00 14.6 3.1 0.02 6.00 24.5 8.7 0.02 8.00 31.8 14.6 0.02 10.00 37.119.9 0.02 12.00 41.2 24.5 0.02 16.00 46.9 31.8 0.02 20.00 50.6 37.1 0.044.00 6.2 0.3 0.04 6.00 17.4 2.2 0.04 8.00 29.2 6.2 0.04 10.00 39.8 11.50.04 12.00 49.0 17.4 0.04 16.00 63.5 29.2 0.04 20.00 74.2 39.8 0.06 4.002.0 0.0 0.06 6.00 9.2 0.4 0.06 8.00 20.1 2.0 0.06 10.00 32.1 5.0 0.0612.00 43.8 9.2 0.06 16.00 64.6 20.1 0.06 20.00 81.6 32.1 0.08 4.00 0.50.0 0.08 6.00 4.4 0.1 0.08 8.00 12.3 0.5 0.08 10.00 23.0 1.9 0.08 12.0034.8 4.4 0.08 16.00 58.3 12.3 0.08 20.00 79.7 23.0 0.01 6.00 23.8 10.90.01 9.00 30.9 18.4 0.01 12.00 35.1 23.8 0.01 15.00 38.0 27.8 0.01 18.0040.0 30.9 0.01 24.00 42.7 35.1 0.01 30.00 44.4 38.0 0.02 6.00 21.9 4.60.02 9.00 36.8 13.0 0.02 12.00 47.6 21.9 0.02 15.00 55.7 29.9 0.02 18.0061.7 36.8 0.02 24.00 70.3 47.6 0.02 30.00 76.0 55.7 0.04 6.00 9.2 0.40.04 9.00 26.1 3.3 0.04 12.00 43.8 9.2 0.04 15.00 59.8 17.2 0.04 18.0073.5 26.1 0.04 24.00 95.3 43.8 0.04 30.00 111.3 59.8 0.06 6.00 2.9 0.00.06 9.00 13.9 0.6 0.06 12.00 30.2 2.9 0.06 15.00 48.1 7.4 0.06 18.0065.7 13.9 0.06 24.00 96.9 30.2 0.06 30.00 122.3 48.1 0.08 6.00 0.8 0.00.08 9.00 6.6 0.1 0.08 12.00 18.5 0.8 0.08 15.00 34.4 2.9 0.08 18.0052.1 6.6 0.08 24.00 87.6 18.5 0.08 30.00 119.5 34.4

The above Table WW shows examples of amounts of therapeutic agent thatcan be placed in the therapeutic device 100 for release, and the amountscan correspond to ranges of an amount. For example, the amount can bewithin a range of two or more values of Table WW, for example within arange from about 6 to about 9 mg of ranibizumab. The amount of thetherapeutic agent such as ranibizumab can be more or less than theamounts shown in Table WW.

Concentrations, Reservoir Container Volumes and Amounts of Ranibizumab

Based on the teachings described herein, amounts of ranibizumab can beinjected into device 100 in many ways so as to provide an intendedamount of therapeutic agent at or above an target amount for an extendedtime, such as 3 months or 6 months, for example. The porous structure ofdevice 150 may comprise a sintered porous material having improvedstability, for example as described with reference to Table VV.

Ranibizumab can be provided for injection into the therapeutic devicebased on a lyophilized powder that can be mixed and diluted to a desiredconcentration. Table X shows concentrations of ranibizumab formulations.Similar formulations can be provided with many therapeutic agents asdescribed herein. Intermediate concentrations to the values shown inTable X may be used, and also values above and below the values shown inTable X. The European approval of ranibizumab indicates that alyophilized form was initially used, and this lyophilized ranibizumabcan be diluted to many appropriate concentrations as described herein.The European approval indicates that the frozen drug substance can bediluted to make the final drug product, such that concentrations of thedrug higher than that in the current approved European product can beachieved in accordance with the teachings as described herein. (SeeEuropean Medicine Agency, Scientific Discussion; retrievable from theInternet;<http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Scientific_Discussion/human/000715/WC500043550.pdf,EMEA 2007, 54 pages total.)

The concentration of diluted ranibizumab can be within a range fromabout 10 mg/mL to about 600 mg/mL, for example. And the concentrationcan be within a range corresponding to a first value of Table X and asecond value of Table X for example within a range from about 230 toabout 260 mg/mL as shown in Table X. A person of ordinary skill in theart can conduct experiments to determine the value based on theteachings described herein.

TABLE X Concentrations of ranibizumab suitable for injection.Concentration mg/ml 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150160 170 180 190 200 210 220 230 240 250 260 270 280 290 300 310 320 330340 350 360 370 380 390 400 410 420 430 440 450 460 470 480 490 500 510520 530 540 550 560 570 580 590 600

Based on the teachings described herein, many amounts of therapeuticagent can be released above an intended target amount for an intendedextended time, and many amounts of Lucentis can be used to provide theintended amount.

Table YY shows examples of formulations and RRI such that that amountsof Ranibizumab can be released at 90 and 180 days so as to provide arate of release continuously above a target amount from the time ofinjection to the time shown in Table YY. These amounts can be combinedwith over injection above the amount of reservoir capacity to release abolus and with exchange as described herein, for example.

TABLE YY Amounts of Ranibizumab Release at 90 and 180 days for deviceamounts from about 0.1 mg to about 30 mg Ranibizumab. pds vol conc rateat 90 days rate at 180 days Ml rri mg/ml mg protein ug/day ug/day 0.010.01 10 0.10 0.4 0.2 0.01 0.02 10 0.10 0.4 0.1 0.01 0.04 10 0.10 0.2 0.00.01 0.06 10 0.10 0.0 0.0 0.01 0.08 10 0.10 0.0 0.0 0.015 0.01 10 0.150.5 0.3 0.015 0.02 10 0.15 0.6 0.2 0.015 0.04 10 0.15 0.4 0.1 0.015 0.0610 0.15 0.2 0.0 0.015 0.08 10 0.15 0.1 0.0 0.02 0.01 10 0.20 0.6 0.40.02 0.02 10 0.20 0.8 0.4 0.02 0.04 10 0.20 0.7 0.2 0.02 0.06 10 0.200.5 0.0 0.02 0.08 10 0.20 0.3 0.0 0.025 0.01 10 0.25 0.6 0.5 0.025 0.0210 0.25 0.9 0.5 0.025 0.04 10 0.25 1.0 0.3 0.025 0.06 10 0.25 0.8 0.10.025 0.08 10 0.25 0.6 0.0 0.03 0.01 10 0.30 0.7 0.5 0.03 0.02 10 0.301.0 0.6 0.03 0.04 10 0.30 1.2 0.4 0.03 0.06 10 0.30 1.1 0.2 0.03 0.08 100.30 0.9 0.1 0.04 0.01 10 0.40 0.7 0.6 0.04 0.02 10 0.40 1.2 0.8 0.040.04 10 0.40 1.6 0.7 0.04 0.06 10 0.40 1.6 0.5 0.04 0.08 10 0.40 1.5 0.30.05 0.01 10 0.50 0.7 0.6 0.05 0.02 10 0.50 1.3 0.9 0.05 0.04 10 0.501.9 1.0 0.05 0.06 10 0.50 2.0 0.8 0.05 0.08 10 0.50 2.0 0.6 0.01 0.01 400.40 1.6 0.7 0.015 0.01 40 0.60 2.1 1.2 0.02 0.01 40 0.80 2.3 1.6 0.0250.01 40 1.00 2.5 1.9 0.03 0.01 40 1.20 2.7 2.1 0.04 0.01 40 1.60 2.8 2.30.05 0.01 40 2.00 3.0 2.5 0.01 0.02 40 0.40 1.5 0.3 0.015 0.02 40 0.602.5 0.9 0.02 0.02 40 0.80 3.2 1.5 0.025 0.02 40 1.00 3.7 2.0 0.03 0.0240 1.20 4.1 2.5 0.04 0.02 40 1.60 4.7 3.3 0.05 0.02 40 2.00 5.1 3.7 0.010.04 40 0.40 0.6 0.0 0.015 0.04 40 0.60 1.7 0.2 0.02 0.04 40 0.80 2.90.6 0.025 0.04 40 1.00 4.0 1.1 0.03 0.04 40 1.20 4.9 1.7 0.04 0.04 401.60 6.4 2.9 0.05 0.04 40 2.00 7.4 4.0 0.01 0.06 40 0.40 0.2 0.0 0.0150.06 40 0.60 0.9 0.0 0.02 0.06 40 0.80 2.0 0.2 0.025 0.06 40 1.00 3.20.5 0.03 0.06 40 1.20 4.4 0.9 0.04 0.06 40 1.60 6.5 2.0 0.05 0.06 402.00 8.2 3.2 0.01 0.08 40 0.40 0.1 0.0 0.015 0.08 40 0.60 0.4 0.0 0.020.08 40 0.80 1.2 0.1 0.025 0.08 40 1.00 2.3 0.2 0.03 0.08 40 1.20 3.50.4 0.04 0.08 40 1.60 5.8 1.2 0.05 0.08 40 2.00 8.0 2.3 0.01 0.01 1001.00 4.0 1.8 0.01 0.02 100 1.00 3.6 0.8 0.01 0.04 100 1.00 1.5 0.1 0.010.06 100 1.00 0.5 0.0 0.01 0.08 100 1.00 0.1 0.0 0.015 0.01 100 1.50 5.13.1 0.015 0.02 100 1.50 6.1 2.2 0.015 0.04 100 1.50 4.3 0.5 0.015 0.06100 1.50 2.3 0.1 0.015 0.08 100 1.50 1.1 0.0 0.02 0.01 100 2.00 5.9 4.00.02 0.02 100 2.00 7.9 3.6 0.02 0.04 100 2.00 7.3 1.5 0.02 0.06 100 2.005.0 0.5 0.02 0.08 100 2.00 3.1 0.1 0.025 0.01 100 2.50 6.3 4.6 0.0250.02 100 2.50 9.3 5.0 0.025 0.04 100 2.50 10.0 2.9 0.025 0.06 100 2.508.0 1.2 0.025 0.08 100 2.50 5.7 0.5 0.03 0.01 100 3.00 6.7 5.1 0.03 0.02100 3.00 10.3 6.1 0.03 0.04 100 3.00 12.3 4.3 0.03 0.06 100 3.00 10.92.3 0.03 0.08 100 3.00 8.7 1.1 0.04 0.01 100 4.00 7.1 5.9 0.04 0.02 1004.00 11.7 7.9 0.04 0.04 100 4.00 15.9 7.3 0.04 0.06 100 4.00 16.1 5.00.04 0.08 100 4.00 14.6 3.1 0.05 0.01 100 5.00 7.4 6.3 0.05 0.02 1005.00 12.7 9.3 0.05 0.04 100 5.00 18.6 10.0 0.05 0.06 100 5.00 20.4 8.00.05 0.08 100 5.00 19.9 5.7 0.01 0.01 200 2.00 7.9 3.6 0.015 0.01 2003.00 10.3 6.1 0.02 0.01 200 4.00 11.7 7.9 0.025 0.01 200 5.00 12.7 9.30.03 0.01 200 6.00 13.3 10.3 0.04 0.01 200 8.00 14.2 11.7 0.05 0.01 20010.00 14.8 12.7 0.01 0.02 200 2.00 7.3 1.5 0.015 0.02 200 3.00 12.3 4.30.02 0.02 200 4.00 15.9 7.3 0.025 0.02 200 5.00 18.6 10.0 0.03 0.02 2006.00 20.6 12.3 0.04 0.02 200 8.00 23.4 15.9 0.05 0.02 200 10.00 25.318.6 0.01 0.04 200 2.00 3.1 0.1 0.015 0.04 200 3.00 8.7 1.1 0.02 0.04200 4.00 14.6 3.1 0.025 0.04 200 5.00 19.9 5.7 0.03 0.04 200 6.00 24.58.7 0.04 0.04 200 8.00 31.8 14.6 0.05 0.04 200 10.00 37.1 19.9 0.01 0.06200 2.00 1.0 0.0 0.015 0.06 200 3.00 4.6 0.2 0.02 0.06 200 4.00 10.1 1.00.025 0.06 200 5.00 16.0 2.5 0.03 0.06 200 6.00 21.9 4.6 0.04 0.06 2008.00 32.3 10.1 0.05 0.06 200 10.00 40.8 16.0 0.01 0.08 200 2.00 0.3 0.00.015 0.08 200 3.00 2.2 0.0 0.02 0.08 200 4.00 6.2 0.3 0.025 0.08 2005.00 11.5 1.0 0.03 0.08 200 6.00 17.4 2.2 0.04 0.08 200 8.00 29.2 6.20.05 0.08 200 10.00 39.8 11.5 0.01 0.01 400 4.00 15.9 7.3 0.015 0.01 4006.00 20.6 12.3 0.02 0.01 400 8.00 23.4 15.9 0.025 0.01 400 10.00 25.318.6 0.03 0.01 400 12.00 26.7 20.6 0.04 0.01 400 16.00 28.5 23.4 0.050.01 400 20.00 29.6 25.3 0.01 0.02 400 4.00 14.6 3.1 0.015 0.02 400 6.0024.5 8.7 0.02 0.02 400 8.00 31.8 14.6 0.025 0.02 400 10.00 37.1 19.90.03 0.02 400 12.00 41.2 24.5 0.04 0.02 400 16.00 46.9 31.8 0.05 0.02400 20.00 50.6 37.1 0.01 0.04 400 4.00 6.2 0.3 0.015 0.04 400 6.00 17.42.2 0.02 0.04 400 8.00 29.2 6.2 0.025 0.04 400 10.00 39.8 11.5 0.03 0.04400 12.00 49.0 17.4 0.04 0.04 400 16.00 63.5 29.2 0.05 0.04 400 20.0074.2 39.8 0.01 0.06 400 4.00 2.0 0.0 0.015 0.06 400 6.00 9.2 0.4 0.020.06 400 8.00 20.1 2.0 0.025 0.06 400 10.00 32.1 5.0 0.03 0.06 400 12.0043.8 9.2 0.04 0.06 400 16.00 64.6 20.1 0.05 0.06 400 20.00 81.6 32.10.01 0.08 400 4.00 0.5 0.0 0.015 0.08 400 6.00 4.4 0.1 0.02 0.08 4008.00 12.3 0.5 0.025 0.08 400 10.00 23.0 1.9 0.03 0.08 400 12.00 34.8 4.40.04 0.08 400 16.00 58.3 12.3 0.05 0.08 400 20.00 79.7 23.0 0.01 0.01600 6.00 23.8 10.9 0.015 0.01 600 9.00 30.9 18.4 0.02 0.01 600 12.0035.1 23.8 0.025 0.01 600 15.00 38.0 27.8 0.03 0.01 600 18.00 40.0 30.90.04 0.01 600 24.00 42.7 35.1 0.05 0.01 600 30.00 44.4 38.0 0.01 0.02600 6.00 21.9 4.6 0.015 0.02 600 9.00 36.8 13.0 0.02 0.02 600 12.00 47.621.9 0.025 0.02 600 15.00 55.7 29.9 0.03 0.02 600 18.00 61.7 36.8 0.040.02 600 24.00 70.3 47.6 0.05 0.02 600 30.00 76.0 55.7 0.01 0.04 6006.00 9.2 0.4 0.015 0.04 600 9.00 26.1 3.3 0.02 0.04 600 12.00 43.8 9.20.025 0.04 600 15.00 59.8 17.2 0.03 0.04 600 18.00 73.5 26.1 0.04 0.04600 24.00 95.3 43.8 0.05 0.04 600 30.00 111.3 59.8 0.01 0.06 600 6.002.9 0.0 0.015 0.06 600 9.00 13.9 0.6 0.02 0.06 600 12.00 30.2 2.9 0.0250.06 600 15.00 48.1 7.4 0.03 0.06 600 18.00 65.7 13.9 0.04 0.06 60024.00 96.9 30.2 0.05 0.06 600 30.00 122.3 48.1 0.01 0.08 600 6.00 0.80.0 0.015 0.08 600 9.00 6.6 0.1 0.02 0.08 600 12.00 18.5 0.8 0.025 0.08600 15.00 34.4 2.9 0.03 0.08 600 18.00 52.1 6.6 0.04 0.08 600 24.00 87.618.5 0.05 0.08 600 30.00 119.5 34.4

FIG. 36A shows amounts of ranibizumab released at about 90 days for a100 mg/mL formulation of Ranibizumab and the corresponding reservoirchamber volume from about 10 uL to about 50 uL and the corresponding RRIfrom about 0.01 to about 0.08;

FIG. 36B shows amounts of ranibizumab released at about 180 days for a100 mg/mL formulation of Ranibizumab and the corresponding reservoirchamber volume from about 10 uL to about 50 uL and the corresponding RRIfrom about 0.01 to about 0.08;

FIG. 36C shows amounts of ranibizumab released at about 90 days for a 10mg/mL formulation of Ranibizumab and the corresponding reservoir chambervolume from about 10 uL to about 50 uL and the corresponding RRI fromabout 0.01 to about 0.08;

FIG. 36D shows amounts of ranibizumab released at about 180 days for a10 mg/mL formulation of Ranibizumab and the corresponding reservoirchamber volume from about 10 uL to about 50 uL and the corresponding RRIfrom about 0.01 to about 0.08;

The above data show that smaller RRIs can provide tuned optimal releaserates as the device volume is decreased, for example tuned to a targetamount released per day and as can be seen with reference to FIGS. 36Aand 36B. The rate of release can be directly proportional to theconcentration loaded into the device, for example as seen with referenceto FIGS. 36B and 36D.

FIG. 37 shows vitreous humor concentration profiles corresponding toranibizumab formulations of 40 mg/mL and 100 mg/mL injected into thetherapeutic device. These concentration profiles were determined withmodeling and calculations as described herein. These values are shownfor an RRI=0.02, a device volume=25 uL, and 100% refill exchangeefficiency. The other parameters such as the diffusion coefficient aredescribed herein. The concentration for the 100 mg/mL injections rangefrom about 40 ug/mL to about 25 ug/mL, and the concentrations for 40mg/mL injections range from about 15 ug/mL to about 10 ug/mL. Forintermediate concentrations of the injected formulation, the values canbe in between those shown for 40 mg/mL and 100 mg/mL. The sequentialinjections can provide treatment for an extended time, for example oneyear.

Example A Measured Release Rate Profiles for Ranibizumab (Lucentis™)Formulations of 40 and 100 mg/mL from Therapeutic Devices and PorousTitanium Fit Structures Corresponding to a Device Half Life of 100 Days

The Device effective Half-life with Ranibizumab=100 days. The volume ofthe device reservoir in this example was 25 uL, and the RRI was about0.02 for a diffusion coefficient of Ranibizumab of 1×10⁻⁶ cm²/s.

Drug Release Studies were performed using ranibizumab formulations of 40or 100 mg/mL. The Ranibizumab was formulated in histidine, withtrehalose dehydrate, and polysorbate 20, in accordance with U.S. patentapplication Ser. No. 12/554,194, Pub. No. 2010/0015157, entitled“Antibody Formulations”, the full disclosure of which is incorporatedherein by reference.

Devices were fabricated using the following method. A vessel was madefrom two subassemblies and a porous frit structure as described herein.The porous frit structure had a thickness of about 0.04 in, and an OD ofabout 0.03 in. The intended RRI was about 0.02 based on gas flowmeasurements and manufacturing as described herein. The implantabledevices were manufactured in accordance with the teachings as describedherein.

Devices were filled with formulation using a 33 G needle (TSK) and astandard tuberculin 1-cc syringe (BD). Excess liquid that had exited theporous sintered frit structure during filling was removed by use of alab tissue and submerging in phosphate buffered saline (PBS, Sigma) and0.02% sodium azide as a preservative. Each device was suspended in thecenter of a 1.5 mL microcentrifuge tube by use of a fixture. The tubewas filled with 0.5 mL receiver fluid; i.e., PBS that had been degassedto minimize bubble formation. At selected times, the device was removedfrom the receiver fluid and placed in a new tube containing freshreceiver fluid. For the first time points that were collected withinshort time intervals, the concentration of Ranibizumab in the receiverfluid was determined using a Micro BCA™ Protein Assay Kit (Pierce) and aMicroplate reader (Molecular Devices). For the later time points, thesample concentrations were higher and concentration was determined by UV(Perkin Elmer Lambda 35). Drug release rates were calculated frommeasured concentration, the volume of the receiver fluid and theduration of the collection interval. Drug release rate profiles wereplotted at the average elapsed time for each collection interval. RRIwas determined via a least squares fit to the model.

Each formulation was filled into ten devices. Some devices were stoppedat 3 and 4 months (n=3 each), leaving four that underwent drug releasetesting for 180 days.

Table Z1 shows the measured RRI and the corresponding max, min andstandard deviations for the devices receiving 40 and 100 mg/mLformulations. The measured mean RRI for both 40 and 100 mg/mLformulations was 0.02, with a standard deviation of 0.002 and 0.001 forthe 40 and 100 mg/mL formulations, respectively. The mean RRI of 0.02and release rates show that the therapeutic device 100 can provide thetherapeutic agent device half life of approximately 100 days.

TABLE Z1 RRI (mm) Formulation (mg/mL) 40 100 Mean 0.024 0.021 SD 0.0020.001 Min 0.021 0.018 Max 0.027 0.023

FIG. 37A shows release of Ranibizumab formulations to 180 days from atherapeutic device comprising an RRI of 0.02 and a volume of 25 uLcorresponding to an effective half life of the therapeutic agent in thedevice of 100 days. The injection of 40 mg/mL to the 25 uL devicecorresponds to 1 mg of ranibizumab injected into the reservoir chamberof the device and 100 mg/mL corresponds to 2.5 mg of ranibizumabinjected into the reservoir chamber of the device.

Example B Measured Release Rate Profiles for Ranibizumab (Lucentis™)Formulations of 100 mg/mL from Therapeutic Devices and Porous TitaniumFrit Structures Corresponding to a Device Half Life of 250 Days

Devices were fabricated as described above with reference to Example A.The titanium porous fit structures had a thickness of 0.031 in and an ODof 0.031. The intended RRI was about 0.008 based on gas flowmeasurements and manufacturing as described herein. The therapeuticdevice reservoir volume was about 25 uL. The effective half-life forthese devices was about 250 days.

The formulation was filled into five devices and all underwent drugrelease testing for 180 days.

Table Z2 shows the measured RRI and the corresponding max, min andstandard deviations for the devices receiving the 100 mg/mLformulations. The mean RRI of 0.008 and release rates show that thetherapeutic device 100 can provide the therapeutic agent device halflife of approximately 250 days.

TABLE Z2 Measured RRI of Therapeutic Devices RRI (mm) Formulation(mg/mL) 100 Mean 0.008 SD 0.001 Min 0.007 Max 0.009

Table Z3A shows release of Ranibizumab at 90 and 180 days for thetherapeutic devices having the 100 day half life. These data correspondto the tuned reservoir volume and release rate of the porous structureas described herein, for example with reference to the 90 and 180 dayrelease rates of FIGS. 36A and 36B, respectively.

TABLE Z3A Release rates of Ranibizumab 100 mg/mL Rate 40 mg/mL Rate Day90 180 90 180 Average 9.51 5.13 5.52 2.42 SD 0.54 0.10 0.05 0.09 Min8.83 5.02 5.46 2.32 Max 10.28 5.26 5.56 2.52 n = 7 4 7 4

FIG. 37B shows release of Ranibizumab to 180 days from a therapeuticdevice comprising an RRI of 0.008 and a volume of 25 uL corresponding toan effective half life of the therapeutic agent in the device of 250days.

TABLE Z3B Release of Ranibizumab at 90 and 175 days for the therapeuticdevices having the 250 day half life. Day 100 mg/mL Rate 90 180 Average5.59 4.51 SD 0.26 0.16 Min 5.29 4.37 Max 5.89 4.75 n = 5 5

The of data FIG. 37B and Table Z3B show that therapeutic amounts of atleast about 4 to 5 ug/day can be released for at least about 180 days,for example 5.6 ug/day and 4.5 ug/day at 90 and 180 days, respectively.While the devices corresponding to FIG. 37A were tuned to providemaximal delivery rates at 4-6 months, the devices corresponding to FIG.37B were tuned to provide maximal delivery rates at approximately 1year.

Example C Measured Release Rate Profiles for Ranibizumab (Lucentis™)Formulations of 40 and 100 mg/mL from Therapeutic Devices and PorousTitanium Fit Structures Corresponding to a Device Half Life of 100 Days

Therapeutic devices having stainless steel porous frit structures andformulations were prepared in accordance with Examples A and B. Thedevices had volumes of 25 uL and an RRI of 0.02.

Pressure decay tests of the assembled porous frit structures wereconducted as described herein.

Eighteen devices were injected with the 100 mg/mL formulation and 18devices were injected with the 40 mg/mL formulation. However,measurements of some devices were stopped for other assays every 4months so only 6 devices for each formulation have release data through180 days. The rate of release was measured for 16 weeks, and the amountrelease after each 2 week interval determined. These data show extendedrelease of therapeutic amounts to 16 weeks for each of the 100 mg/mL and40 mg/mL formulations. The data indicates a measured rate of 3.5 and 8.1ug/day at 15 weeks, for the 40 and 100 mg/mL formulation injections,respectively.

FIG. 37C shows release of ranibizumab from a population of devicesreceiving injections of 40 mg/mL formulation and 100 mg/mL formulation.

The data of FIGS. 37A to 37C show that the therapeutic agent comprisingranibizumab can be released from the therapeutic devices in accordancewith the teachings as described herein, for example with reference toFIGS. 32A-32D, 36A-36D and Tables WW, X, YY, for example.

As used herein, like identifiers denote like structural elements and/orsteps.

Any structure or combination of structures or method steps or componentsor combinations thereof as described herein can be combined inaccordance with embodiments as described herein, based on the knowledgeof one of ordinary skill in the art and teachings described herein. Inaddition, any structure or combination of structures or method steps orcomponents or combinations thereof as described herein may bespecifically excluded from any embodiments, based on the knowledge ofone of ordinary skill in the art and the teachings described herein.

While the exemplary embodiments have been described in some detail, byway of example and for clarity of understanding, those of skill in theart will recognize that a variety of modifications, adaptations, andchanges may be employed. Hence, the scope of the present inventionshould be limited solely by the appended claims.

TABLE 1A Therapeutic Agent List Molecular Generic Name Brands(Companies) Category Indication Weight 2-Methoxyestradiol (PalomaPharmaceuticals) Angiogenesis inhibitors AMD analogs 3-aminothalidomide13-cis retinoic acid Accutane TM (Roche Pharmaceuticals) A0003 (AqumenBioPharmaceuticals) A0003 AMD A5b1 integrin (Jerini Ophthalmic);(Ophthotech) Inhibitors of a5b1 integrin AMD inhibitor AbarelixPlenaxis ™ (Praecis Pharmaceuticals) Anti-Testosterone Agents; Forpalliative treatment of advanced 37731 Antineoplastic Agents prostatecancer. Abatacept Orencia ™ (Bristol-Myers Squibb) Antirheumatic AgentsFor the second line reduction of the signs 37697 and symptoms ofmoderate-to-severe active rheumatoid arthritis, inducing inducing majorclinical response, slowing the progression of structural damage, andimproving physical function in adult patients who have AbciximabReoPro ™; ReoPro ™ (Centocor) Anticoagulants; For treatment ofmyocardial infarction, 42632 Antiplatelet Agents adjunct to percutaneous178oronary intervention, unstable angina ABT-578 (Abbott Laboratories)Limus Immunophilin Binding Compounds Acetonide Adalimumab Humira ™(Abbott Laboratories) Antirheumatic Agents; Uveitis, AMD 25645Immunomodulatory Agents Aldesleukin Proleukin ™; Proleukin ™ (ChironAntineoplastic Agents For treatment of adults with metastatic 61118Corp) renal cell carcinoma Alefacept Amevive ™ Immunomodulatory Fortreatment of moderate to severe 42632 Agents; chronic plaque psoriasisImmunosuppressive Agents Alemtuzumab Campath ™; Campath ™ (ILEXAntineoplastic Agents For treatment of B-cell chronic 6614Pharmaceuticals LP); MabCampath ™ lymphocytic leukemiaAlpha-1-proteinase Aralase ™ (Baxter); Prolastin ™ Enzyme ReplacementFor treatment of panacinar emphysema 28518 inhibitor (TalecrisBiotherapeutics C formerly Agents Bayer) Alteplase Activase ™ (GenentechInc) Thrombolytic Agents For management of acute myocardial 54732infarction, acute ischemic strok and for lysis of acute pulmonary emboliAMG-1470 Anakinra Kineret ™ (Amgen Inc) Anti-Inflammatory Agents, Forthe treatment of adult rheumatoid 65403 Non-Steroidal; arthritis.Antirheumatic Agents; Immunomodulatory Agents Anecortave acetateAngiostatin Anistreplase Eminase ™ (Wulfing Pharma GmbH) ThrombolyticAgents For lysis of acute pulmonary emboli, 54732 intracoronary emboliand management of myocardial infarction Anti-angiogenesis (Eyecopharm)Anti-angiogenesis AMD peptides peptides Anti-angiogenesis (TRACONPharma) Anti-angiogenesis AMD antibodies, antibodies TRC093, TRC105Anti-angiogeric Icon-1 ™ (Iconic Therapeutics) Anti-angiogeric AMDbifunctional protein bifunctional protein, Icon-1 Anti-endothelialgrowth factor Antihemophilic Advate ™; Alphanate ™; Bioclate ™;Coagulants; Thrombotic For the treatment of hemophilia A, von 70037Factor Helixate ™; Helixate FS ™; Hemofil Agents Willebrand diseae andFactor XIII M ™; Humate-P ™; Hyate:C ™; deficiency Koate-HP ™;Kogenate ™; Kogenate FS ™; Monarc-M ™; Monoclate-P ™; ReFacto ™;Xyntha ™ Antithymocyte Genzyme); Thymoglobulin ™ Immunomodulatory AgentsFor prevention of renal transplant 37173 globulin (SangStat Medicalrejection Anti-hypertensive (MacuCLEAR) Anti-hypertensive MC1101 AMDMC1101 Anti-platelet devired growth factor Anti-VEGF (Neurotech);Avastin ™ (NeoVista) Anti-VEGF AMD AP23841 (Ariad) Limus ImmunophilinBinding Compounds ARC1905 Ophthotech Complement Cascade Inhibitor(Factor C5) Aprotinin Trasylol ™ Antifibrinolytic Agents Forprophylactic use to reduce 90569 perioperative blood loss and the needfor blood transfusion in patients undergoing cardiopulmonary bypass inthe course of coronary artery bypass graft surgery who are at anincreased risk for blood loss and blood transfusio ArcitumomabCEA-Scan ™ Diagnostic Agents; For imaging colorectal tumors 57561Imaging Agents Asparaginase Elspar ™ (Merck & Co. Inc) AntineoplasticAgents For treatment of acute lympocytic 132.118 leukemia andnon-Hodgkins lymphoma Axitinib Tyrosine Kinase Inhibitors 386Basiliximab Simulect ™ (Novartis Immunomodulatory For prophylactictreatment of kidney 61118 Pharmaceuticals) Agents; transplant rejectionImmunosuppressive Agents Becaplermin Regranex ™; Regranex ™ (OMJAnti-Ulcer Agents; Topical For topical treatment of skin ulcers (from123969 Pharmaceuticals) diabetes) Bevacizumab Avastin ™; Avastin ™(Genentech Inc) Antiangiogenesis Agents; For treatment of metastaticcolorectal 27043 Antineoplastic Agents cancer Bivalirudin Angiomax ™;Angiomax ™ (Medicines Anticoagulants; For treatment of heparin-induced70037 Co or MDCO); Angiox ™ Antithrombotic Agents thrombocytopeniaBortezomib Proteosome Inhibitors Bosutinib Tyrosine Kinase Inhibitors530 Botulinum Toxin BOTOX ™ (Allegran Inc); BOTOX Anti-Wrinkle Agents;For the treatment of cervical dystonia in 23315 Type A Cosmetic ™(Allegran Inc); Botox ™; Antidystonic Agents; adults to decrease theseverity of Dysport ™ Neuromuscular Blocking abnormal head position andneck pain Agents associated with cervical dystonia. Also for thetreatment of severe primary axillary hyperhidrosis that is inadequatelymanaged with topical Botulinum Toxin Myobloc ™ (Solstice Neurosciences);Antidystonic Agents For the treatment of patients with cervical 12902Type B Neurobloc ™ (Solstice Neurosciences) dystonia to reduce theseverity of abnormal head position and neck pain associated withcervical dystonia. C5 inhibitor (Jerini Ophthalmic); (Ophthotech)Inhibitors of C5 AMD Cal101 Calistoga PI3Kdelta Inhibitor AMD, DMECanstatin Capromab ProstaScint ™ (Cytogen Corp) Imaging Agents Fordiagnosis of prostate cancer and 84331 detection of intra-pelvicmetastases Captopril ACE Inhibitors CCI-779 (Wyeth) Limus ImmunophilinBinding Compounds Cediranib Tyrosine Kinase Inhibitors 450 CelecoxibCyclooxygenase Inhibitors Cetrorelix Cetrotide ™ Hormone Antagonists;For the inhibition of premature LH surges 78617 Infertility Agents inwomen undergoing controlled ovarian stimulation Cetuximab Erbitux ™;Erbitux ™ (ImClone Antineoplastic Agents For treatment of metastaticcolorectal 42632 Systems Inc) cancer. Choriogonadotropin Novarel ™;Ovidrel ™; Pregnyl ™; Fertility Agents; For the treatment of femaleinfertility 78617 alfa Profasi ™ Gonadotropins Cilary neurotrophic(Neurotech) Cilary neurotrophic factor AMD factor Coagulation FactorBenefix ™ (Genetics Institute) Coagulants; Thrombotic For treatment ofhemophilia (Christmas 267012 IX Agents disease). Coagulation factorNovoSeven ™ (Novo Nordisk) Coagulants; Thrombotic For treatment ofhemorrhagic 54732 VIIa Agents complications in hemophilia A and BColchicines Collagenase Cordase ™; Santyl ™ (Advance Anti-Ulcer Agents;Topical For treatment of chronic dermal ulcers 138885 Biofactures Corp);Xiaflextm ™ and severe skin burns Complement factor (Optherion);(Taligen Therapeutics) Complement factor H AMD, Geographic Atrophy Hrecombinant recombinant Compstatin (Potentia Pharmaceuticals) ComplementFactor C3 AMD derivative peptide, Inhibitors; Compstatin POT-4Derivative Peptides Corticotropin ACTH ™; Acethropan ™; Acortan ™;Diagnostic Agents For use as a diagnostic agent in the 33927 Acthar ™;Exacthin ™; H.P. Acthar screening of patients presumed to have Gel ™;Isactid ™; Purified cortrophin adrenocortical insufficiency. gel ™;Reacthin ™; Solacthyl ™; Tubex Cosyntropin Cortrosyn ™; Synacthendepot ™ Diagnostic Agents For use as a diagnostic agent in the 33927screening of patients presumed to have adrenocortical insufficiency.Cyclophilins Limus Immunophilin Binding Compounds Cyclosporine Gengraf ™(Abbott labs); Neoral ™ Antifungal Agents; For treatment of transplantrejection, 32953 (Novartis); Restasis ™; Restasis ™ AntirheumaticAgents; rheumatoid arthritis, severe psoriasis (Allergan Inc);Sandimmune ™ Dermatologic Agents; (Novartis); Sangcya ™ EnzymeInhibitors; Immunomodulatory Agents; Immunosuppressive Agents DaclizumabZenapax ™ (Hoffmann-La Roche Inc) Immunomodulatory For prevention ofrenal transplant 61118 Agents; rejection; Uveitis ImmunosuppressiveAgents Darbepoetin alfa Aranesp ™ (Amgen Inc.) Antianemic Agents For thetreatment of anemia (from renal 55066 transplants or certain HIVtreatment) Dasatinib Tyrosine Kinase Inhibitors 488 DefibrotideDasovas ™; Noravid ™; Prociclide ™ Antithrombotic Agents Defibrotide isused to treat or prevent a 36512 failure of normal blood flow (occlusivevenous disease, OVD) in the liver of patients who have had bone marrowtransplants or received certain drugs such as oral estrogens,mercaptopurine, and many others. Denileukin diftitox Ontak ™Antineoplastic Agents For treatment of cutaneous T-cell 61118 lymphomaDesmopressin Adiuretin ™; Concentraid ™; Antidiuretic Agents; For themanagement of primary nocturnal 46800 Stimate ™ Hemostatics; Renalenuresis and indicated as antidiuretic Agents replacement therapy in themanagement of central diabetes insipidus and for the management of thetemporary polyuria and polydipsia following head trauma or surgery inthe pitu Dexamethasone Ozurdex ™ (Allergan) Glucocorticoid DME,inflammation, macular edema 392 following branch retinal vein occlusion(BRVO) or central retinal vein occlusion (CRVO) DiclofenacCyclooxygenase Inhibitors Dithiocarbamate NFκB Inhibitor Dornase AlfaDilor ™; Dilor-400 ™; Lufyllin ™; Enzyme Replacement For the treatmentof cystic fibrosis. 7656 (double Lufyllin-400 ™; Neothylline ™; Agentsstrand) Pulmozyme ™ (Genentech Inc) Drotrecogin alfa Xigris ™; Xigris ™(Eli Lilly & Co) Antisepsis Agents For treatment of severe sepsis 267012Eculizumab Soliris ™; Soliris ™ (Alexion Complement Cascade AMD 188333Pharmaceuticals) Inhibitor (Factor C5) Efalizumab Raptiva ™; Raptiva ™(Genentech Inc) Immunomodulatory For the treatment of adult patientswith 128771 Agents; moderate to severe chronic plaque Immunosuppressivepsoriasis, who are candidates for Agents phototherapy or systemictherapy. Endostatin Enfuvirtide Fuzeon ™; Fuzeon ™ (Roche Anti-HIVAgents; HIV For treatment of HIV AIDS 16768 Pharmaceuticals) FusionInhibitors Epoetin alfa Epogen ™ (Amgen Inc.); Epogin ™ AntianemicAgents For treatment of anemia (from renal 55066 (Chugai); Epomax ™(Elanex); transplants or certain HIV treatment) Eprex ™ (Janssen-Cilag.Ortho Biologics LLC); NeoRecormon ™ (Roche); Procrit ™ (Ortho Biotech);Recormon ™ (Roche) Eptifibatide Integrilin ™; Integrilin ™ (MillenniumAnticoagulants; For treatment of myocardial infarction and 7128 Pharm)Antiplatelet Agents; acute coronary syndrome. Platelet AggregationInhibitors Erlotinib Tyrosine Kinase Inhibitors 393 Etanercept Enbrel ™;Enbrel ™ (Immunex Corp) Antirheumatic Agents; Uveitis, AMD 25645Immunomodulatory Agents Everolimus Novartis Limus Immunophilin AMDBinding Compounds, mTOR Exenatide Byetta ™; Byetta ™ (Amylin/Eli Lilly)Indicated as adjunctive therapy to 53060 improve glycemic control inpatients with Type 2 diabetes mellitus who are taking metformin, asulfonylurea, or a combination of both, but have not achieved adequateglycemic control. FCFD4514S Genentech/Roche Complement Cascade AMD,Geographic Atrophy Inhibitor (Factor D) Felypressin Felipresina ™[INN-Spanish]; Renal Agents; For use as an alternative to adrenaline as46800 Felipressina ™ [DCIT]; Felypressin ™ Vasoconstrictor Agents a187ocalizing agent, provided that local [USAN:BAN:INN]; Felypressine ™ischaemia is not essential. [INN-French]; Felypressinum ™ [INN- Latin];Octapressin ™ Fenretinide Sirion/reVision Therapeutics Binding ProteinAntagonist AMD, Geographic Atrophy for Oral Vitamin A FilgrastimNeupogen ™ (Amgen Inc.) Anti-Infective Agents; Increases leukocyteproduction, for 28518 Antineutropenic Agents; treatment in non-myeloidImmunomodulatory Agents cancer, neutropenia and bone marrow transplantFK605-binding Limus Immunophilin proteins, FKBPs Binding CompoundsFluocinolone Retisert ™ (Bausch & Lomb); Glucocorticoid Retinalinflammation, diabetic macular 453 Acetonide Iluvien ™ edema (AlimeraSciences, Inc.) Follitropin beta Follistim ™ (Organon); Gonal F ™;Fertility Agents For treatment of female infertility 78296 Gonal-F ™Fumagillin Galsulfase Naglazyme ™; Naglazyme ™ Enzyme Replacement Forthe treatment of adults and children 47047 (BioMarin Pharmaceuticals)Agents with Mucopolysaccharidosis VI. Gefitinib Tyrosine KinaseInhibitors 447 Gemtuzumab Mylotarg ™; Mylotarg ™ (Wyeth) AntineoplasticAgents For treatment of acute myeloid leukemia 39826 ozogamicinGlatiramer Acetate Copaxone ™ Adjuvants, Immunologic; For reduction ofthe frequency of relapses 29914 Immunosuppressive in patients withRelapsing-Remitting Agents Multiple Sclerosis. Glucagon GlucaGen ™ (NovoNordisk); Antihypoglycemic Agents For treatment of severe hypoglycemia,54009 recombinant Glucagon ™ (Eli Lilly) also used in gastrointestinalimaging Goserelin Zoladex ™ Antineoplastic Agents; Breast cancer;Prostate carcinoma; 78617 Antineoplastic Agents, Endometriosis HormonalHuman Serum Albutein ™ (Alpha Therapeutic Corp) Serum substitutes Fortreatment of severe blood loss, 39000 Albumin hypervolemia,hypoproteinemia Hyaluronidase Vitragan ™; Vitrase ™; Vitrase ™ (IstaAnesthetic Adjuvants; For increase of absorption and distribution 69367Pharma) Permeabilizing Agents of other injected drugs and forrehydration Ibritumomab Zevalin ™ (IDEC Pharmaceuticals) AntineoplasticAgents For treatment of non-Hodgkin's lymphoma 33078 IdursulfaseElaprase ™ (Shire Pharmaceuticals) Enzyme Replacement For the treatmentof Hunter syndrome in 47047 Agents adults and children ages 5 and older.Imatinib Tyrosine Kinase Inhibitors AMD, DME 494 Immune globulinCivacir ™; Flebogamma ™ (Instituto Anti-Infectives; For treatment ofimmunodeficiencies, 42632 Grifols SA); Gamunex ™ (TalecrisImmunomodulatory Agents thrombocytopenic purpura, KawasakiBiotherapeutics) disease, gammablobulinemia, leukemia, bone transplantInfliximab Remicade ™ (Centocor Inc) Immunomodulatory Uveitis, AMD 25645Agents; Immunosuppressive Agents Insulin Glargine Lantus ™ HypoglycemicAgents For treatment of diabetes (type I and II) 156308 recombinantInsulin Lyspro Humalog ™ (Eli Lily); Insulin Lispro Hypoglycemic AgentsFor treatment of diabetes (type I and II) 154795 recombinant (Eli Lily)Insulin recombinant Novolin R ™ (Novo Nordisk) Hypoglycemic Agents Fortreatment of diabetes (type I and II) 156308 Insulin, porcine IletinII ™ Hypoglycemic Agents For the treatment of diabetes (type I and156308 II) Interferon Interferon Alfa-2a, Roferon A ™ (Hoffmann-La RocheAntineoplastic Agents; For treatment of chronic hepatitis C, hairy 57759Recombinant Inc); Veldona ™ (Amarillo Antiviral Agents cell leukemia,AIDS-related Kaposi's Biosciences) sarcoma, and chronic myelogenousleukemia. Also for the treatment of oral warts arising from HIVinfection. Interferon Alfa-2b, Intron A ™ (Schering Corp) AntineoplasticAgents; For the treatment of hairy cell leukemia, 57759 RecombinantAntiviral Agents; malignant melanoma, and AIDS-related ImmunomodulatoryAgents Kaposi's sarcoma. Interferon alfacon-1 Advaferon ™; Infergen ™(InterMune Antineoplastic Agents; For treatment of hairy cell leukemia,57759 Inc) Antiviral Agents; malignant melanoma, and AIDS-relatedImmunomodulatory Agents Kaposi's sarcoma Interferon alfa-n1 Wellferon ™(GlaxoSmithKline) Antiviral Agents; For treatment of venereal or genitalwarts 57759 Immunomodulatory Agents caused by the Human Papiloma VirusInterferon alfa-n3 Alferon ™ (Interferon Sciences Inc.); AntineoplasticAgents; For the intralesional treatment of 57759 Alferon LDO ™; AlferonN Antiviral Agents; refractory or recurring external Injection ™Immunomodulatory Agents condylomata 190cuminate. Interferon beta-1bBetaseron ™ (Chiron Corp) Antiviral Agents; For treatment ofrelapsing/remitting 57759 Immunomodulatory Agents multiple sclerosisInterferon gamma- Actimmune ™; Actimmune ™ Antiviral Agents; Fortreatment of Chronic granulomatous 37835 1b (InterMune Inc)Immunomodulatory Agents disease, Osteopetrosis Lapatinib Tyrosine KinaseInhibitors 581 Lepirudin Refludan ™ Anticoagulants; For the treatment ofheparin-induced 70037 Antithrombotic Agents; thrombocytopeniaFibrinolytic Agents Lestaurtinib Tyrosine Kinase Inhibitors 439Leuprolide Eligard ™ (Atrix Labs/QLT Inc) Anti-Estrogen Agents; Fortreatment of prostate cancer, 37731 Antineoplastic Agents endometriosis,uterine fibroids and premature puberty Lutropin alfa Luveris ™ (Serono)Fertility Agents For treatment of female infertility 78617 MecaserminIncrelex ™; Increlex ™ (Tercica); Iplex For the long-term treatment ofgrowth 154795 failure in pediatric patients with Primary IGFD or with GHgene deletion who have developed neutralizing antibodies to GH. It isnot indicated to treat Secondary IGFD resulting from GH deficiency,malnutrition, hypoth Menotropins Repronex ™ Fertility Agents Fortreatment of female infertility 78617 Methotrexate ImmunomodulatoryUveitis, DME mTOR inhibitors Muromonab Orthoclone OKT3 ™ (Ortho Biotech)Immunomodulatory For treatment of organ transplant 23148 Agents;recipients, prevention of organ rejection Immunosuppressive AgentsNatalizumab Tysabri ™ Immunomodulatory Agents For treatment of multiplesclerosis. 115334 Nepafenac Cyclooxygenase Inhibitors NesiritideNatrecor ™ Cardiac drugs For the intravenous treatment of patients118921 with acutely decompensated congestive heart failure who havedyspnea at rest or with minimal activity. Nilotinib Tyrosine KinaseInhibitors 530 NS398 Cyclooxygenase Inhibitors Octreotide Atrigel ™;Longastatin ™; Anabolic Agents; For treatment of acromegaly and 42687Sandostatin ™; Sandostatin LAR ™; Antineoplastic Agents, reduction ofside effects from cancer Sandostatin LAR ™ (Novartis) Hormonal;Gastrointestinal chemotherapy Agents; Hormone Replacement AgentsOmalizumab Xolair ™ (Genentech Inc) Anti-Asthmatic Agents; For treatmentof asthma caused by 29596 Immunomodulatory Agents allergies OprelvekinNeumega ™; Neumega ™ (Genetics Coagulants; Thrombotics Increases reducedplatelet levels due to 45223 Institute Inc) chemotherapy OspAlipoprotein LYMErix ™ (SmithKline Beecham) Vaccines For prophylactictreatment of Lyme 95348 Disease OT-551 (Othera) Anti-oxidant eyedrop AMDOxytocin Oxytocin ™ (BAM Biotech); Pitocin ™ Anti-tocolytic Agents; Toassist in labor, elective labor induction, 12722 (Parke-Davis);Syntocinon ™ (Sandoz) Labor Induction Agents; uterine contractioninduction Oxytocics Palifermin Kepivance ™ (Amgen Inc) AntimucositisAgents For treatment of mucositis (mouth sores) 138885 PalivizumabSynagis ™ Antiviral Agents For treatment of respiratory diseases 63689casued by respiratory syncytial virus Panitumumab Vectibix ™; Vectibix ™(Amgen) Antineoplastic Agents For the treatment of EGFR-expressing,134279 metastatic colorectal carcinoma with disease progression on orfollowing fluoropyrimidine-, oxaliplatin-, and irinotecan-containingchemotherapy regimens. PDGF inhibitor (Jerini Ophthalmic); (Ophthotech)Inhibitors of PDGF AMD PEDF (pigment epithelium derived factor)Pegademase Adagen ™ (Enzon Inc.) Enzyme Replacement For treatment ofadenosine deaminase 36512 bovine Agents deficiency Pegaptanib Macugen ™Oligonucleotide For the treatment of neovascular (wet) 103121age-related macular degeneration. Pegaspargase Oncaspar ™ (Enzon Inc)Antineoplastic Agents For treatment of acute lymphoblastic 132.118leukemia Pegfilgrastim Neulasta ™ (Amgen Inc.) Anti-Infective Agents;Increases leukocyte production, for 28518 Antineutropenic Agents;treatment in non-myeloid cancer, Immunomodulatory Agents neutropenia andbone marrow transplant Peginterferon alfa- Pegasys ™ (Hoffman-La RocheInc) Antineoplastic Agents; For treatment of hairy cell leukemia, 577592a Antiviral Agents; malignant melanoma, and AIDS-relatedImmunomodulatory Agents Kaposi's sarcoma. Peginterferon alfa- PEG-Intron(Schering Corp); Unitron Antineoplastic Agents; For the treatment ofchronic hepatitis C in 57759 2b PEG ™ Antiviral Agents; patients notpreviously treated with Immunomodulatory Agents interferon alpha whohave compensated liver disease and are at least 18 years of age.Pegvisomant Somavert ™ (Pfizer Inc) Anabolic Agents; Hormone Fortreatment of acromegaly 71500 Replacement Agents PentoxifyllinePerindozril ACE Inhibitors Pimecrolimus Limus Immunophilin BindingCompounds PKC (protein kinase C) inhibitors POT-4 Potentia/AlconComplement Cascade AMD Inhibitor (Factor C3) Pramlintide Symlin ™;Symlin ™ (Amylin For the mealtime treatment of Type I and 16988Pharmaceuticals) Type II diabetes in combination with standard insulintherapy, in patients who have failed to achieve adequate glucose controlon insulin monotherapy. Proteosome Velcade ™ Proteosome inhibitorsinhibitors Pyrrolidine Quinopril ACE Inhibitors Ranibizumab Lucentis ™For the treatment of patients with 27043 neovascular (wet) age-relatedmacular degeneration. Rapamycin (MacuSight) Limus Immunophilin AMD(siroliums) Binding Compounds Rasburicase Elitek ™; Elitek ™(Sanofi-Synthelabo Antihyperuricemic Agents For treatment ofhyperuricemia, reduces 168.11 Inc); Fasturtec ™ elevated plasma uricacid levels (from chemotherapy) Reteplase Retavase ™ (Centocor);Retavase ™ Thrombolytic Agents For lysis of acute pulmonary emboli,54732 (Roche) intracoronary emboli and management of myocardialinfarction Retinal stimulant Neurosolve ™ (Vitreoretinal Retinalstimulants AMD Technologies) Retinoid(s) Rituximab MabThera ™; Rituxan ™Antineoplastic Agents For treatment of B-cell non-Hodgkins 33078lymphoma (CD20 positive) RNAI (RNA interference of angiogenic factors)Rofecoxib Vioxx ™; Ceoxx ™; Ceeoxx ™ (Merck Cyclooxygenase Inhibitors &Co.) Rosiglitazone Thiazolidinediones Ruboxistaurin Eli Lilly ProteinKinase C (PKC)-b DME, diabetic peripheral retinopathy 469 InhibitorSalmon Calcitonin Calcimar ™; Miacalcin ™ (Novartis) AntihypocalcemicAgents; For the treatment of post-menopausal 57304 AntiosteporoticAgents; osteoporosis Bone Density Conservation Agents SargramostimImmunex ™; Leucomax ™ (Novartis); Anti-Infective Agents; For thetreatment of cancer and bone 46207 Leukine ™; Leukine ™ (BerlexAntineoplastic Agents; marrow transplant Laboratories Inc)Immunomodulatory Agents SAR 1118 SARCode Immunomodulatory Agent Dry eye,DME, conjunctivitis SDZ-RAD Limus Immunophilin Binding CompoundsSecretin SecreFlo ™; Secremax ™, SecreFlo ™ Diagnostic Agents Fordiagnosis of pancreatic exocrine 50207 (Repligen Corp) dysfunction andgastrinoma Selective inhibitor of the factor 3 complement cascadeSelective inhibitor of the factor 5 complement cascade SemaxanibTyrosine Kinase Inhibitors 238 Sermorelin Geref ™ (Serono Pharma)Anabolic Agents; Hormone For the treatment of dwarfism, prevention 47402Replacement Agents of HIV-induced weight loss Serum albumin Megatope ™(IsoTex Diagnostics) Imaging Agents For determination of total blood and39000 iodinated plasma volumes SF1126 Semafore PI3k/mTOR Inhibition AMD,DME Sirolimus (MacuSight) Limus Immunophilin AMD reformulation BindingCompounds (rapamycin) siRNA molecule (Quark Pharmaceuticals) siRNAmolecule synthetic AMD synthetic, FTP- 801i-14 Somatropin BioTropin ™(Biotech General); Anabolic Agents; Hormone For treatment of dwarfism,acromegaly 71500 recombinant Genotropin ™ (Pfizer); Humatrope ™Replacement Agents and prevention of HIV-induced weight (Eli Lilly);Norditropin ™ (Novo loss Nordisk); Nutropin ™ (Genentech Inc.);NutropinAQ ™ (Genentech Inc.); Protropin ™ (Genentech Inc.); Saizen ™(Serono SA); Serostim ™; Serostim ™ (Serono SA); Tev- Tropin ™ (GATE)Squalamine Streptokinase Streptase ™ (Aventis Behringer ThrombolyticAgents For the treatment of acute evolving 90569 GmbH) transmuralmyocardial infarction, pulmonary embolism, deep vein thrombosis,arterial thrombosis or embolism and occlusion of arteriovenous cannulaeSunitinib Tyrosine Kinase Inhibitors 398 TA106 Taligen ComplementCascade AMD Inhibitor (Factor B) Tacrolimus Limus Immunophilin BindingCompounds Tenecteplase TNKase ™ (Genentech Inc) Thrombolytic Agents Fortreatment of myocardial infarction and 54732 lysis of intracoronaryemboli Teriparatide Apthela ™; Forsteo ™; Forteo ™; Bone Density For thetreatment of osteoporosis in men 66361 Fortessa ™; Opthia ™; Optia ™;Conservation Agents and postmenopausal women who are at Optiah ™;Zalectra ™; Zelletra ™ high risk for having a fracture. Also used toincrease bone mass in men with primary or hypogonadal osteoporosis whoare at high risk for fracture. Tetrathiomolybdate Thalidomide CelgeneAnti-inflammatory, Anti- Uveitis proliferative Thyrotropin AlfaThyrogen ™ (Genzyme Inc) Diagnostic Agents For detection of residueal orrecurrent 86831 thyroid cancer Tie-1 and Tie-2 kinase inhibitorsToceranib Tyrosine Kinase Inhibitors 396 Tositumomab Bexxar ™ (CorixaCorp) Antineoplastic Agents For treatment of non-Hodgkin's lymphoma33078 (CD20 positive, follicular) TPN 470 analogue TrastuzumabHerceptin ™ (Genentech) Antineoplastic Agents For treatment ofHER2-positive 137912 pulmonary breast cancer Triamcinolone Triesence ™Glucocorticoid DME, For treatment of inflammation of the 435 acetonideretina Troglitazone Thiazolidinediones Tumistatin UrofollitropinFertinex ™ (Serono S.A.) Fertility Agents For treatment of femaleinfertility 78296 Urokinase Abbokinase ™; Abbokinase ™ (AbbottThrombolytic Agents For the treatment of 199ulmonary 90569 Laboratories)embolism, coronary artery thrombosis and IV catheter clearanceVandetanib Tyrosine Kinase Inhibitors 475 Vasopressin Pitressin ™;Pressyn ™ Antidiuretics; Oxytocics; For the treatment of enuresis,polyuria, 46800 Vasoconstrictor Agents diabetes insipidus, polydipsiaand oesophageal varices with bleeding Vatalanib Tyrosine KinaseInhibitors 347 VEGF receptor kinase inhibitor VEGF Trap Aflibercept ™(Regneron Genetically Engineered DME, cancer, retinal vein occlusion,96600 Pharmaceuticals, Bayer HealthCare Antibodies choroidalneovascularization, delay AG) wound healing, cancer treatment VisualCycle (Acucela) Visual Cycle Modulator AMD Modulator ACU- 4229Vitamin(s) Vitronectin receptor antagonists Volociximab Ophthotechalpha5beta1 Integrin AMD Inhibitor XL765 Exelixis/Sanofi-AventisPI3k/mTOR Inhibition AMD, DME

1. A method of treating an eye having a vitreous humor, the methodcomprising: injecting at least about 3.5 mg of ranibizumab into atherapeutic device implanted in the eye, the therapeutic device having achamber volume sized to store no more than about 1.5 mg of ranibizumab,such that at least about 2 mg of ranibizumab is released from thetherapeutic device to the vitreous humor of the eye as a bolusinjection.
 2. The method claim 1, the further comprising: injecting atleast about 4 mg of ranibizumab into the therapeutic device implanted inthe eye, such that at least about 2 mg of ranibizumab is released fromthe therapeutic device to the vitreous humor of the eye as a secondbolus injection.
 3. A method of treating an eye having a vitreous humor,the method comprising: injecting a first amount of a therapeutic agentinto a therapeutic device implanted in the eye; and injecting a secondamount of the therapeutic agent into the therapeutic device implanted inthe eye; wherein, the second amount is less than the first amount basedon a portion of the amount of therapeutic agent contained in thetherapeutic device when the second amount is injected.
 4. The method ofclaim 3, wherein the second amount is less than the first amount basedon a mixing ratio of the second amount with the portion.
 5. The methodof claim 3, wherein the second amount is injected at least about onemonth after the first amount is injected.
 6. A method of treating an eyehaving a vitreous humor, the method comprising: injecting a first amountof a therapeutic agent into a therapeutic device implanted in the eye,the first amount corresponding to a first injection volume greater thana chamber volume of the therapeutic device such that a first portion ofthe first amount is passed through the chamber into the vitreous humoras a first bolus injection and a second contained portion is containedin the chamber and released for an extended time; and injecting a secondamount of the therapeutic agent into the therapeutic device implanted inthe eye, the second amount corresponding to a second injection volumegreater than the chamber volume of the therapeutic device, such that afirst portion of the second amount is passed through the chamber intothe vitreous humor as a second bolus injection and a second containedportion is contained in the chamber and released for an extended time;wherein the second amount is less than the first amount such that thesecond bolus injection has no more therapeutic agent than the firstbolus injection.
 7. A method of treating an eye having a vitreous humor,the method comprising: injecting an amount of therapeutic agent into areservoir of a therapeutic device, the reservoir having a substantiallyfixed volume coupled to a porous structure, wherein the amount isgreater than the substantially fixed volume such that a first portion ofthe amount is released into the vitreous humor of the eye as a bolusinjection and a second portion of the amount is retained in thereservoir, wherein the second portion is released from the porousstructure at amounts lower than amounts of the first portion are removedfrom the eye such that the bolus injection corresponds to a maximumconcentration of the therapeutic agent in the eye.
 8. The method ofclaim 7, wherein the maximum concentration comprises no more than a peakconcentration of corresponding to an amount of the bolus injection.
 9. Amethod of treating an eye having a vitreous humor and an establishedsafe bolus amount of a therapeutic agent, the method comprising:injecting a first amount of a therapeutic agent into a therapeuticdevice implanted in the eye; and injecting a second amount of thetherapeutic agent into the therapeutic device implanted in the eye;wherein, a portion of the first amount of therapeutic agent is containedin the therapeutic device when the second amount is injected such that asecond bolus is released from the therapeutic device to the vitreoushumor, the second bolus comprising a second amount of the therapeuticagent greater than the established safe bolus amount.
 10. The method ofclaim 9 wherein the second amount comprises an incremental increase inexposure to the therapeutic agent.
 11. The method of claim 9 furthercomprising injecting additional bolus amounts above the second amount toestablish a second safe bolus amount.
 12. The method of claim 9 furthercomprising removing the therapeutic agent from the therapeutic devicebased on a negative response to the second amount of the therapeuticagent, wherein the therapeutic agent is exchanged with a solutionsubstantially lacking the therapeutic agent.
 13. An apparatus to treatan eye an eye with a therapeutic agent having an established safeamount, the apparatus comprising: an injector having a volume of liquidcomprising an amount of therapeutic agent; and a therapeutic devicehaving a chamber volume sized smaller than the injector volume torelease a bolus of the therapeutic agent.
 14. A sustained drug deliveryformulation comprising a therapeutic agent wherein the therapeutic agentis contained in a reservoir of the device of claim 13, and wherein thetherapeutic agent has a half-life within the reservoir when implanted,the half life within the reservoir substantially greater than acorresponding half-life of the at least one of the therapeutic agentwhen injected directly into the vitreous of an eye.
 15. The formulationof claim 14, wherein the device can be configured by selection of thereservoir volume and a porous structure with an appropriate rate releaseindex to achieve the desired effective half-life.
 16. The formulation ofclaim 15, wherein the rate release index is within a range from about0.001 to about
 5. 17. The formulation of claim 15, wherein the raterelease index is within a range from about 0.002 to about
 5. 18. Theformulation of claim 15, wherein the rate release index is from about0.01 to about
 5. 19. The formulation of claim 14, wherein the firsttherapeutic agent is a VEGF-inhibitor and the second therapeutic agentis a inflammatory response inhibitor.
 20. A sustained drug deliveryformulation to treat a patient of a population, the formulationcomprising: a therapeutic agent, wherein the therapeutic agent has ahalf-life within the eye corresponding to a half life of the therapeuticagent injected into a device implanted in the eye.
 21. A method oftreating an eye, the method comprising: injecting an amount therapeuticagent into a therapeutic device, the amount within a range from about0.01 mg to about 50 mg.
 22. The method of claim 21, wherein the amountis within a range is from about 0.1 mg to about 30 mg.
 23. An apparatusto treat an eye, the apparatus comprising an amount of formulationcorresponding to an amount of therapeutic agent, the amount within arange from about 0.01 mg to about 50 mg; and a therapeutic device havinga reservoir chamber and porous structure tuned to receive the amount offormulation corresponding to the amount of therapeutic agent.
 24. Themethod of claim 23, wherein the amount is within a range is from about0.1 mg to about 30 mg.
 25. An apparatus to treat an eye with atherapeutic agent, the apparatus comprising: an injector having a volumeof fluid comprising an amount of therapeutic agent; and a therapeuticdevice comprising a reservoir chamber, the reservoir chamber having avolume sized to receive the amount of therapeutic agent; wherein theamount of therapeutic agent is placed in the reservoir chamber.
 26. Theapparatus of claim 25 wherein the fluid comprises a concentration ofranibizumab within a range from about 40 mg/mL to about 200 mg/mL. 27.The apparatus of claim 25 wherein the fluid comprises a concentration ofranibizumab of within a range from about 40 mg/ml to about 100 mg/mL.28. The apparatus of claim 25 wherein the injector is configured toplace the amount with no substantial bolus.
 29. The apparatus of claim25 wherein the injector is configured to place the amount with anexchange efficiency of at least about 80%.
 30. The apparatus of claim 25wherein the injector comprises an injection lumen to inject thetherapeutic and a vent to receive fluid of the chamber, the therapeuticdevice comprising a reservoir chamber to release the therapeutic agent,and wherein the vent comprises a resistance to flow substantially lowerthan a resistance to flow of the porous structure of the therapeuticdevice so as to inhibit a bolus of the therapeutic agent through theporous structure.
 31. An apparatus to treat an eye an eye with atherapeutic agent, the apparatus comprising: injecting a volume of afluid comprising an amount of therapeutic agent into a therapeuticdevice comprising a reservoir chamber, the reservoir chamber having avolume sized to receive the amount of therapeutic agent, wherein theamount of therapeutic agent is placed in the reservoir chamber.
 32. Themethod of claim 31 wherein the injector is configured to place theamount with an exchange efficiency of at least about 80%.
 33. The methodof claim 31 wherein the amount is placed in the reservoir chamber withno substantial bolus of the fluid comprising the therapeutic agentthrough the porous structure.
 34. A method of treating an eye having asclera, the method comprising: coupling a removal tool to a retentionstructure of an expandable therapeutic device coupled to the sclera, theexpandable therapeutic device comprising a support coupled to a flexiblebarrier; advancing an elongate structure through an incision of thesclera and along the support to decrease a cross-sectional size of thesupport coupled to the flexible barrier; and removing the supportthrough the incision in the sclera with the decreased cross-sectionalsize.
 35. The method of claim 34 wherein the elongate structurecomprises one or more of a needle, a shaft, a mandrel or a wire.
 36. Themethod of claim 34 wherein a length of the support is increased todecrease the cross-sectional size.
 37. The method of claim 36 whereinthe expandable therapeutic device comprises a distal portion having astop coupled to the support and wherein the elongate structure contactsthe stop and advances the stop to increase the length of the support anddecrease the cross-sectional size of the support.
 38. The method ofclaim 37 wherein the stop comprises a portion of the support or a porousstructure to release the therapeutic agent.
 39. The method of claim 34wherein the support coupled to the flexible barrier comprises anelongate narrow profile configuration for insertion through the incisionand an expanded wide profile configuration, the expanded wide profileconfiguration of the support coupled to the flexible barrier defining achamber having a substantially constant volume to release thetherapeutic agent through a porous structure into a vitreous humor ofthe eye.
 40. The method of claim 39 wherein the expandable therapeuticdevice comprises a penetrable barrier on a proximal portion coupled tothe chamber and a porous structure on a distal portion coupled to thechamber and wherein the elongate structure is advanced through thepenetrable barrier to decrease the cross-sectional size.
 41. The methodof claim 39 wherein the expandable therapeutic device is advanced intothe incision with a cannula such that the support coupled to theflexible barrier comprises the narrow elongate profile within thecannula and expands to the wide profile configuration when passedthrough the incision.
 42. An apparatus to treat an eye having a scleraand vitreous humor, the device comprising: an expandable therapeuticdevice comprising a retention structure to couple to the sclera, apenetrable barrier and a flexible support coupled to a flexible barrier,wherein the flexible support is expandable from a first elongate narrowprofile configuration having a first length and a first cross-sectionalsize to a second wide profile configuration having a second length and asecond cross-sectional size, the second wide profile configurationdefining a chamber having a substantially constant volume when placed inthe eye, the first length greater than the second length, the firstcross-sectional size smaller than the second cross-sectional size,wherein the flexible support and the flexible barrier have sufficientlyflexibility so as to increase the length from the second length to thefirst length and decrease the cross-sectional size from the second sizeto the first size when an elongate structure is advanced through thepenetrable barrier.
 43. The apparatus of claim 42 further comprising aremoval apparatus comprising the elongate structure and jaws to coupleto the retention structure and wherein the elongate structure comprisesone or more of a needle, a shaft, a mandrel or a wire.
 44. The apparatusof claim 42 wherein the porous structure comprises a rigid porousstructure affixed to a distal end of the support to release thetherapeutic agent into a vitreous humor of the eye for an extended timeand wherein the flexible support and flexible barrier compriseflexibility sufficient to increase the length increases from the secondlength to the first length when the elongate structure contacts therigid porous structure.
 45. The apparatus of claim 42 wherein thesupport comprises a plurality of flexible struts that extend axiallyfrom the retention structure to an annular flange sized to support theporous structure on the distal end of device, and wherein the flexiblestruts comprise are space apart when the device comprises the secondexpanded profile configuration to define the chamber having thesubstantially constant volume.